Abstracts
Initially the trajectory of the historical forerunners and conceptions of senile dementia are briefly presented, being highlighted the name of Alois Alzheimer who provided clinical and neuropathological indicators to differentiate a group of patients with Senile dementia. Alzheimer's examination of Auguste D’s case, studied by him with Bielschowsky’s silver impregnation technique, permitted to identify a pathological marker, the intraneuronal neurofibrillary tangles, characterizing a new disease later named after him by Kraepelin – Alzheimer’s disease. Over the time this disorder became one of the most important degenerative dementing disease, reaching nowadays a status that may be considered as epidemic.
dementia; Senile dementia; hystory of medicine; Alzheimer; Alzheimer’ disease
Incialmente é apresentada brevemente a trajetória histórica dos precursores e dos conceitos da demência senil, sendo destacado o nome de Alois Alzheimer que forneceu indicadores clínicos e neuropatológicos para diferenciar um grupo de pacientes com Demência senil. O exame de Alzheimer do caso de Auguste D, estudado por ele com a técnica de impregnação argêntica de Bielschowsky, permitiu identificar um marcador patológico, os emaranhados neurofibrilares intraneuronais, caracterizando uma nova doença, mais tarde denominada com seu nome por Kraepelin – doença de Alzheimer. Com o passar do tempo esta desordem tornou-se uma das mais importantes doenças demenciante degenerativa, alcançando, na atualidade, um status que pode ser considerado como epidêmico.
demência; Demência senil; história da medicina; Alzheimer; doença de Alzheimer
Alzheimer’s 100th anniversary of death raises an opportunity to
remember his contributions to the study of senile dementia and allied
disorders. Senile dementia has a very long history. Greek philosophers such
as Plato and Aristotle were imbued with the conviction that old age is
inseparable from mental failure. This belief was further elaborated, as by
Cicero, who suggested that an active mental life could prevent or at least
postpone mental decline11 Berchtold NC, Cotman CW. Evolution in the
conceptualization of dementia and Alzheimer's disease:
Greco-Roman period to the 1960s. Neurobiol Aging.
1998;19(3):173-89.
http://dx.doi.org/10.1016/S0197-4580(98)00052-9
https://doi.org/10.1016/S0197-4580(98)00...
.
In the 18th century, Senile dementia was recognized by Cullen as
a “decay of perception and memory, in old age (Amentia
senilis)” (apud11 Berchtold NC, Cotman CW. Evolution in the
conceptualization of dementia and Alzheimer's disease:
Greco-Roman period to the 1960s. Neurobiol Aging.
1998;19(3):173-89.
http://dx.doi.org/10.1016/S0197-4580(98)00052-9
https://doi.org/10.1016/S0197-4580(98)00...
). Later, Phillippe Pinel's asylum
reforms gave the ground to the widespread clinical and pathological
observations on mental disorders, including Senile dementia. In the
19th century, numerous famous names were engaged in the
study of dementing illnesses, and among them, Alzheimer11 Berchtold NC, Cotman CW. Evolution in the
conceptualization of dementia and Alzheimer's disease:
Greco-Roman period to the 1960s. Neurobiol Aging.
1998;19(3):173-89.
http://dx.doi.org/10.1016/S0197-4580(98)00052-9
https://doi.org/10.1016/S0197-4580(98)00...
.
ALZHEIMER: LIFE, PARTNERSHIPS AND ACHIEVEMENTS
Aloysius "Alois" Alzheimer (June, 14th, 1864-December,
19th, 1915) (Figure 1), German psychiatrist and pathologist, was
born in the Bavarian town of Marktbreit. He obtained his medical
degree at the Würzburg University (1887), and within months
began working at the Hospital for the Mentally Ill and Epileptics,
in Frankfurt22 Caramelli P, Viel AH. 100 anos da doença de
Alzheimer. São Paulo: Segmento Farma;
2006.,33 Costandi M. 100 years of Alzheimer’s disease.
2006 [cited 2014 July 8]. Available from:
http://neurophilosophy.wordpress.com/2006/11/03/100-years-of-alzheimers-disease/
http://neurophilosophy.wordpress.com/200...
,44 Devi G, Quitschke W. Alois Alzheimer, neuroscientist
(1864-1915). Alzheimer Dis Assoc Disord.
1999;13(3):132-7.. He married a
banker's widow, Cecile Geisenheimer, but after seven years she
died, leaving him alone with three children22 Caramelli P, Viel AH. 100 anos da doença de
Alzheimer. São Paulo: Segmento Farma;
2006.,44 Devi G, Quitschke W. Alois Alzheimer, neuroscientist
(1864-1915). Alzheimer Dis Assoc Disord.
1999;13(3):132-7.. Alzheimer died
relatively young, as described by Kraepelin, due to an
“infective angina associated with nephritis and inflammation
of the articulations...” that led to severe renal and
respiratory failure (apud55 Tagarelli A, Piro A, Tagarelli G, Lagonia P,
Quattrone A. Alois Alzheimer: a hundred years after the
discovery of the eponymous disorder. Int J Biomed Sci.
2006;2(2):196-204.).
Alzheimer worked as psychiatrist and pathologist in Frankfurt (1888-1902), at the Municipal asylum; Heidelberg (by 1902), where Franz Nissl assumed the chair of psychiatry previously occupied by Emil Kraepelin; Munich (1903-1912), at the Royal psychiatric hospital, under Kraepelin’s direction; and Breslau (1912-1915), as assistant professor of psychiatry at the Neurological and Psychiatric Clinic of the Friedrich-Wilhelm University55 Tagarelli A, Piro A, Tagarelli G, Lagonia P, Quattrone A. Alois Alzheimer: a hundred years after the discovery of the eponymous disorder. Int J Biomed Sci. 2006;2(2):196-204.. Besides the professional relationship, he entertained a solid companionship with Nissl, which lasted a quarter-century, and an enduring friendship with Kraepelin. He held successfully positions that matched clinical practice and pathology. His pathological knowledge was solid, which he considered essential for the psychiatric study. He was also praised as a teacher and colleague22 Caramelli P, Viel AH. 100 anos da doença de Alzheimer. São Paulo: Segmento Farma; 2006.,44 Devi G, Quitschke W. Alois Alzheimer, neuroscientist (1864-1915). Alzheimer Dis Assoc Disord. 1999;13(3):132-7..
SENILE DEMENTIA UNFOLDINGS
Alzheimer provided numerous contributions to neuropathology, as on acute
alcoholic delirium, pseudo-sclerosis of Westphal-Strümpell,
early dementia, brain tumors, progressive paralysis of young,
epilepsy, encepalitis, chorea of Huntington, General paresis,
arteriosclerotic brain disorders, among others, besides developing
neurohistological stains. With Nissl he published histologic and
histopathological studies of the cerebral cortex. He described for
the first time, in hepatic encephalopathy, a specific cell type
– Alzheimer's type II cell11 Berchtold NC, Cotman CW. Evolution in the
conceptualization of dementia and Alzheimer's disease:
Greco-Roman period to the 1960s. Neurobiol Aging.
1998;19(3):173-89.
http://dx.doi.org/10.1016/S0197-4580(98)00052-9
https://doi.org/10.1016/S0197-4580(98)00...
. Alzheimer and Binswanger may
be recognized as pioneers in the study of vascular brain diseases,
and Alzheimer (among others) established pathological distinction
among them and from syphilis, one of his objectives66 Alzheimer A. Neuere Arbeiten über die Dementia
senilis und die auf atheromatöser Gefässerkrankung
basierenden Hirnkrankheiten. Monatsschr Psychiat Neurol.
1898;3:101-15.
Alzheimer interacted clinically with a 51 years old demented patient,
Auguste D (Deter) (Figure 2),
in 1901. Her ailment initiated with jealousy towards her husband,
followed by memory impairment, disorientation, aphasia, apraxia,
agnosia, paraphrasing, and persecutory delusions. Alzheimer examined
her during five months, when he left the institution, but made
frequent inquiries about her state, which deteriorated considerably
in the last years, until her death, in 1906, at the age of 55
years77 Alzheimer, A. Über eine eigenartige Erkrankung
der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und
phychish-Gerichtliche
Medizin.1907;64:146-8..
Meanwhile, Alzheimer was working on vascular diseases of the brain,
and has already identified, among the senile dementia patients, one
case with primary [cortical] ganglion degeneration
(1898)66 Alzheimer A. Neuere Arbeiten über die Dementia
senilis und die auf atheromatöser Gefässerkrankung
basierenden Hirnkrankheiten. Monatsschr Psychiat Neurol.
1898;3:101-15.
With the notice of Auguste D's death, Alzheimer requested from
his friend Dr. Sioli, director of the Frankfurt Institution, her
medical records and brain. When he received the material,
Bielschowsky has already published, in 1903, a silver impregnation
method that revealed the neurofibrils11 Berchtold NC, Cotman CW. Evolution in the
conceptualization of dementia and Alzheimer's disease:
Greco-Roman period to the 1960s. Neurobiol Aging.
1998;19(3):173-89.
http://dx.doi.org/10.1016/S0197-4580(98)00052-9
https://doi.org/10.1016/S0197-4580(98)00...
,22 Caramelli P, Viel AH. 100 anos da doença de
Alzheimer. São Paulo: Segmento Farma;
2006.. In the
occasion, among others, he counted in his laboratory with two
Italian disciples, Francesco Bonfiglio and Gaetano Perusini, who
colaborated in the analysis and discussion of the case. The
microscopic examination of the histological preparations revealed,
stained in sharp definition with Bielschowsky’s technique, a
novel feature – the presence of thick bundles of neurofibrils
within the cytoplasm of cortical neurons. He also found, dispersed
in the cortex, miliari foci of a peculiar substance, a feature
already known. This case was object of Azheimer’s seminal
presentation of his findings at the 37th Meeting of
South-west German Psychiatrists held in Tübingen, Germany, in
1906, under the title Über eine eigenartige Erkrankung
der Hirnrinde (About a peculiar disease of the
cerebral cortex)22 Caramelli P, Viel AH. 100 anos da doença de
Alzheimer. São Paulo: Segmento Farma;
2006.,
quickly published, in 1907, in the Allgemeine Zeitschrift
für Psychiatrie und psychisch-gerichtliche
Medizin77 Alzheimer, A. Über eine eigenartige Erkrankung
der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und
phychish-Gerichtliche
Medizin.1907;64:146-8.(Box
Box.
Excerpts from Alzheimer’s 1907 paper,
highlighting the histopathological findings of
Auguste D’s material7.
According Alzheimer, “The examination of the brain showed
an evenly atrophic aspect, without macroscopic foci. The
larger cerebral vessels displayed arteriosclerotic
changes”. Further, Alzheimer described the
histopathology of the tissue, in relation to the
neurofibrils, as follows: “The histological
preparations, stained with the Bielschowsky’s silver
method, show very striking changes of the neurofibrils
(displayed in Figures 3A, 3B
and 3C). Inside a cell which otherwise
appears almost normal, one or several fibrils presenting
special thickness and particular impregnability can be seen
(A). In the further course, changed in the same way, many
fibrils arranged close to each other can be noticed. Next,
they assemble to constitute thick bundles, and appear
gradually on the surface of the cell (B). Finally, the
nucleus and the cell disintegrate, and only a tangled bundle
of fibrils indicate the place where previously a neuron was
located (C)”…. “Approximately ¼ to
⅓ of all neurons of the cortex show such changes.
Numerous neurons, especially in the upper cellular layers,
have completely disappeared.” He also described the
senile plaques (as later named), in the following
way: “Dispersed over the entire cortex, specially
numerous in the upper layers, are found small miliary foci
containing deposits of a peculiar material, limited to the
cerebral cortex. This foci may already be observed without
staining, however, they are very refractory to
stains“. Finally, Alzheimer states: “Summing
up, we have here before us a peculiar disease
process”… He states: “Such observations
suggest that we should not feel satisfied, in face of an
unclear clinical case, and spend all efforts to accommodate
it in one of the well-known disease groups. There are,
doubtless, much more psychic ailments then those presented
in our textbooks. Regarding some of such cases, a later
histological examination will permit to determine the
singularity of a given case”. Concluding:
“Then, we progressively will also reach a situation
that will allow to separate single diseases clinically, amid
the great disease groups of our textbooks, permitting a
sharper medical definition”.
). This was the first documented case of a new
presenile dementia subtype, soon named after him, Alzheimer’s
disease, by Kraepelin, as described in the eighth edition of his
Textbook of Psychiatry (1910)22 Caramelli P, Viel AH. 100 anos da doença de
Alzheimer. São Paulo: Segmento Farma;
2006.,33 Costandi M. 100 years of Alzheimer’s disease.
2006 [cited 2014 July 8]. Available from:
http://neurophilosophy.wordpress.com/2006/11/03/100-years-of-alzheimers-disease/
http://neurophilosophy.wordpress.com/200...
,88 Kraepelin E. Psychiatrie: ein Lehrbuch für
Studierende und Ärzte. Leipzig: Barth; 1910 [cited
2014 Jan 1]. Vol 2, p. 627-8. Available from:
http://www2.biusante.parisdescartes.fr/livanc/index.las?cote=63261x02&do=chapitre
http://www2.biusante.parisdescartes.fr/l...
. Thus, Alzheimer achieved
another of his aims, the segregation of dementing disorders
according to their causes, and was fortunate to reveal a new
disease.
According Alzheimer, “The examination of the brain showed an evenly atrophic aspect, without macroscopic foci. The larger cerebral vessels displayed arteriosclerotic changes”. Further, Alzheimer described the histopathology of the tissue, in relation to the neurofibrils, as follows: “The histological preparations, stained with the Bielschowsky’s silver method, show very striking changes of the neurofibrils (displayed in Figures 3A, 3B and 3C). Inside a cell which otherwise appears almost normal, one or several fibrils presenting special thickness and particular impregnability can be seen (A). In the further course, changed in the same way, many fibrils arranged close to each other can be noticed. Next, they assemble to constitute thick bundles, and appear gradually on the surface of the cell (B). Finally, the nucleus and the cell disintegrate, and only a tangled bundle of fibrils indicate the place where previously a neuron was located (C)”…. “Approximately ¼ to ⅓ of all neurons of the cortex show such changes. Numerous neurons, especially in the upper cellular layers, have completely disappeared.” He also described the senile plaques (as later named), in the following way: “Dispersed over the entire cortex, specially numerous in the upper layers, are found small miliary foci containing deposits of a peculiar material, limited to the cerebral cortex. This foci may already be observed without staining, however, they are very refractory to stains“. Finally, Alzheimer states: “Summing up, we have here before us a peculiar disease process”… He states: “Such observations suggest that we should not feel satisfied, in face of an unclear clinical case, and spend all efforts to accommodate it in one of the well-known disease groups. There are, doubtless, much more psychic ailments then those presented in our textbooks. Regarding some of such cases, a later histological examination will permit to determine the singularity of a given case”. Concluding: “Then, we progressively will also reach a situation that will allow to separate single diseases clinically, amid the great disease groups of our textbooks, permitting a sharper medical definition”.
In 1911, Alzheimer published the paper Über eigenartige
Krankheitsfälle des späteren Alters
(About peculiar disease cases in the later age), where he displayed,
for the first time, drawings of the intraneuronal tangles of Auguste
D’s material, classified in several stages (Figure 3). He also described
in a detailed manner another case, Johann F, a 56-year-old male,
hospitalized in Kraepelin’s clinic, who suffered from
presenile dementia99 Alzheimer A. Über eigenartige
Krankheitsfälle des späteren Alters. Zeitschrift
für die Gesamte Neurologie und psychiatrie. 1911
[cited 2013 Ago 2];4:356-85. Available from:
http://www.bium.univ-paris5.fr/histmed/medica/cote?epo1243
http://www.bium.univ-paris5.fr/histmed/m...
.
Drawings of histological preparations of Auguste D's material, stained by Bielschowsky's technique to demonstrate tangles, and their stages, from Alzheimer’s 1911 paper99 Alzheimer A. Über eigenartige Krankheitsfälle des späteren Alters. Zeitschrift für die Gesamte Neurologie und psychiatrie. 1911 [cited 2013 Ago 2];4:356-85. Available from: http://www.bium.univ-paris5.fr/histmed/medica/cote?epo1243
http://www.bium.univ-paris5.fr/histmed/m... : (A) Beginning of the disease; (B) Advanced stage; and (C) Terminal state of the disease.
Auguste D’s material remained unavailable for a long time, being
rediscovered in the archives of the University of Frankfurt,
confirming, almost a century later, Alzheimer’s findings33 Costandi M. 100 years of Alzheimer’s disease.
2006 [cited 2014 July 8]. Available from:
http://neurophilosophy.wordpress.com/2006/11/03/100-years-of-alzheimers-disease/
http://neurophilosophy.wordpress.com/200...
,1010 Graeber MB, Mehraein P. Reanalysis of the first case
of Alzheimer's disease. Eur Arch Psychiatry Clin
Neurosci. 1999;249(3 Suppl):S10-3.
http://dx.doi.org/10.1007/PL00014167
https://doi.org/10.1007/PL00014167...
. This material was further
sudied, not only its histological aspects, but also the genetic
ones1010 Graeber MB, Mehraein P. Reanalysis of the first case
of Alzheimer's disease. Eur Arch Psychiatry Clin
Neurosci. 1999;249(3 Suppl):S10-3.
http://dx.doi.org/10.1007/PL00014167
https://doi.org/10.1007/PL00014167...
.
Over the time Alzheimer’s disease, raised from the position of a infrequent disorder, to become one of the most important degenerative dementing disease, reaching nowadays what can be considered as an epidemic status.
FINAL REMARKS
Alzheimer gave the first steps to break apart the heterogeneous Senile dementia, in the late 19th and early 20th century. He was only able to reveal the identifying marker, the neurofibrillary tangles, thanks to the development of Bielschowsky’s staining technique. These finding, the striking neurofibrillary pathology he identified, besides the already known “miliary foci” (senile plaques], were recognized afterward as markers of the disease that carries Alzheimer’s name.
References
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1Berchtold NC, Cotman CW. Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s. Neurobiol Aging. 1998;19(3):173-89. http://dx.doi.org/10.1016/S0197-4580(98)00052-9
» https://doi.org/10.1016/S0197-4580(98)00052-9 -
2Caramelli P, Viel AH. 100 anos da doença de Alzheimer. São Paulo: Segmento Farma; 2006.
-
3Costandi M. 100 years of Alzheimer’s disease. 2006 [cited 2014 July 8]. Available from: http://neurophilosophy.wordpress.com/2006/11/03/100-years-of-alzheimers-disease/
» http://neurophilosophy.wordpress.com/2006/11/03/100-years-of-alzheimers-disease/ -
4Devi G, Quitschke W. Alois Alzheimer, neuroscientist (1864-1915). Alzheimer Dis Assoc Disord. 1999;13(3):132-7.
-
5Tagarelli A, Piro A, Tagarelli G, Lagonia P, Quattrone A. Alois Alzheimer: a hundred years after the discovery of the eponymous disorder. Int J Biomed Sci. 2006;2(2):196-204.
-
6Alzheimer A. Neuere Arbeiten über die Dementia senilis und die auf atheromatöser Gefässerkrankung basierenden Hirnkrankheiten. Monatsschr Psychiat Neurol. 1898;3:101-15
-
7Alzheimer, A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und phychish-Gerichtliche Medizin.1907;64:146-8.
-
8Kraepelin E. Psychiatrie: ein Lehrbuch für Studierende und Ärzte. Leipzig: Barth; 1910 [cited 2014 Jan 1]. Vol 2, p. 627-8. Available from: http://www2.biusante.parisdescartes.fr/livanc/index.las?cote=63261x02&do=chapitre
» http://www2.biusante.parisdescartes.fr/livanc/index.las?cote=63261x02&do=chapitre -
9Alzheimer A. Über eigenartige Krankheitsfälle des späteren Alters. Zeitschrift für die Gesamte Neurologie und psychiatrie. 1911 [cited 2013 Ago 2];4:356-85. Available from: http://www.bium.univ-paris5.fr/histmed/medica/cote?epo1243
» http://www.bium.univ-paris5.fr/histmed/medica/cote?epo1243 -
10Graeber MB, Mehraein P. Reanalysis of the first case of Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci. 1999;249(3 Suppl):S10-3. http://dx.doi.org/10.1007/PL00014167
» https://doi.org/10.1007/PL00014167
Publication Dates
-
Publication in this collection
Feb 2015
History
-
Received
08 Sept 2014 -
Reviewed
27 Sept 2014 -
Accepted
16 Oct 2014