Alzheimer and vascular brain disease: Senile dementia

Engelhardt, Eliasz; Grinberg, Lea T.

doi:10.1590/1980-57642015DN92000013

Abstracts

Alois Alzheimer is best known for his description of a novel disease, subsequently named after him. However, his wide range of interests also included vascular brain diseases. He described Senile dementia, a highly heterogeneous condition, and was able not only to distinguish it from syphilitic brain disease, but also to discriminate two clinicopathological subtypes, that may be labeled a "arteriosclerotic subtype", comparable to the present clinicopathological continuum of "Vascular cognitive impairment", and another as a "neurodegenerative subtype", characterized by primary [cortical] ganglion cell [nerve cells] degeneration, possibly foreshadowing a peculiar presenile disease that he was to describe some years later and would carry his name. He also considered the possibility of a senile presentation of this disease subtype, which was described by Oskar Fischer a short time later. Considering the clinicopathological overlapping features of the "arteriosclerotic subtype" of Senile dementia with Arteriosclerotic atrophy of the brain, it might be possible to consider that both represent a single condition.

Alzheimer; brain vascular disease; arteriosclerosis; Senile dementia

Alois Alzheimer é conhecido principalmente por sua descrição de uma nova doença, logo designado com seu nome. Entretanto, sua ampla gama de interesses, compreendia também doenças vasculares cerebrais. Descreveu a Demência senil, uma condição muito heterogênea, e foi capaz, não somente distingui-la da doença cerebral sifilítica, como também separar dois subtipos clinicopatológicos que podem ser rotulados como um "subtipo arteriosclerótico", que pode ser relacionado ao atual continuum clinicopatológico do "Comprometimento cognitivo vascular", e um "subtipo neurodegenerativo", caracterizado por degeneração [cortical] primária de células ganglionares [células nervosas], possivelmente prenunciando uma doença peculiar pré-senil, que ele descreveu alguns anos depois e que portaria seu nome. Considerou a possibilidade de uma apresentação senil deste subtipo da doença, que seria descrita por Oskar Fischer pouco tempo depois. Levando em conta os aspectos de sobreposição clinicopatológica do "subtipo arteriosclerótico" da Demência senil com a Atrofia arteriosclerótica do cérebro, poderia ser possível considerar que ambas representariam uma só condição.

Alzheimer; doença vascular cerebral; arteriosclerose; Demência senil

INTRODUCTION

Aloysius [Alois] Alzheimer (1864-1915), was a German psychiatrist and neuropathologist, best known for his description of "neurofibrillary tangles" in brain neurons of a patient with presenile dementia.¹1. Alzheimer A. Uber eine eigenartige Erkrankung derHirnrinde. Allg Z Psychiat phychish-gerichtliche Medizin1907;64:146-148. A short time later this condition received the denomination of "Alzheimer's disease".²2. Kraepelin E. Psychiatrie: ein Lehrbuch für Studierende und Ärzte. Vol II.

Alzheimer's interests were quite wide, including vascular brain diseases. His precursor work greatly contributed toward introducing key knowledge of what would later be incorporated into the field of "Vascular dementia" and related disorders. Although he was not the only scholar to study this subject, he produced very comprehensive concepts, including novel pathological descriptions on vascular brain diseases.³3. Leipzig: Barth, 1910, pp 627-628. [Retrieved from: http://www2.biusante.parisdescartes.fr/livanc/index.las?cote=63261x02&do=chapitre]
http://www2.biusante.parisdescartes.fr/l...

At the time, the dementia definition was somewhat loose, and comprised heterogeneous mental conditions, including General paralysis, melancholia, mania, Senile dementia, varied psychic disorders of the senium, vascular brain diseases, and others.²2. Kraepelin E. Psychiatrie: ein Lehrbuch für Studierende und Ärzte. Vol II. ^, ⁴4. Engelhardt and Grinberg LT. Alzheimer and vascular brain disease: the Arteriosclerotic atrophy of the brain. Dement Neuropsychol 2015;9:81-84. ^, ⁵5. Boller F, Forbes MM. History of dementia and dementia in history: an overview. J Neurol Sci 1998;158:125-133. Alzheimer and numerous famous scientific contemporaries focused on extricating these many disorders according to their etiology, and mainly on differentiating them from the prevalent syphilitic brain disorders.⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... ^, ⁷7. Alzheimer A. Neuere Arbeiten über die Dementia senilis und die auf atheromatöser Gefässerkrankung basierenden Hirnkrankheiten. Monatsschr Psychiat Neurol 1898;3:101-115. This body of work resulted in advances to a field in which knowledge had remained stagnated since Antiquity.⁴4. Engelhardt and Grinberg LT. Alzheimer and vascular brain disease: the Arteriosclerotic atrophy of the brain. Dement Neuropsychol 2015;9:81-84. ^, ⁸8. Román GC. A historical review of the concept of vascular dementia: lessons from the past for the future. Alzheimer Dis Assoc Disord 1999; 13(Suppl 3):S4-S8. ^, ⁹9. Berchtold NC, Cotman CW. Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s. Neurobiol Aging 1998;19:173-189.

The objective of the present paper was to discuss Alzheimer's studies on Senile dementia, a condition to be later subdivided into several independent diseases.

SENILE DEMENTIA

Alzheimer previously mentioned the term Senile dementia (Dementia senilis, senile Demenz) in the main text and discussion of his 1894 paper.¹⁰10. Berrios GE. A Conceptual History in the Nineteenth Century. In: Principles and Practice of Geriatric Psychiatry. 3rd ed. Abou-Saleh MT,Katona CLE, Kumar A eds. Chichester: John Wiley& Sons, 2011, pp 3-6. He further commented, in 1898, about the lack of systematic clinicopathological studies on Senile dementia, yet an abundance of studies on Paralytic dementia (Paralysis).⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... Additionally, he highlighted that most studies on Senile dementia had included conditions that more closely resembled mental disorders of the senium or senile mental impairment (Greisenblödsinn) such as melancholia, mania, depression, among others, which might equally be related to arteriosclerosis, as cited by Kraepelin. Such disorders of the senium could eventually show regressive changes, with feebleness and reduced brain performance, finally evolving to Senile dementia.²2. Kraepelin E. Psychiatrie: ein Lehrbuch für Studierende und Ärzte. Vol II. ^, ⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... Thus, regarding this conceptual heterogeneity, Alzheimer stated that "Senile dementia may develop in the form of extraordinary colorful and richly varied pictures, making it difficult to classify the disease based solely on clinical symptoms, similarly to the challenges in Paralysis".⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85...

Alzheimer discussed the possible underlying pathology of Senile dementia and the correlation with clinical manifestations He cited Weigert's work that demonstrated an elevated number of glia in the upper cortical layers [astrogliosis], and that their processes constituted a dense fiber meshwork in the cerebral grey and white matter. He further suggested a correlation between astrogliosis severity and cognitive decline, highlighting that older brains with milder glial changes may manifest less severe regression of mental performance.⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... However, these changes often reached higher degrees of severity and caused the milder or "silent form" of Senile dementia (stille Form der Dementia senilis), possibly the most frequent mental disorder, found commonly among patients living with their families or in asylums, and rarely in institutions, as also observed by Windscheid.¹¹11. Alzheimer A. Die arteriosklerotische Atrophie des Gehirns. Neurol Centralblatt 1894;13:765-767.

12. Alzheimer A. Die Seelenstörungen auf arteriosklerotischer Grundlage. Allg Z Psychiat 1902;59:695-710. ^- ¹³13. Alzheimer A. Die Seelenstörungen auf arteriosklerotischer Grundlage. Monatsschrift für Psychiat Neurol 1902;12:152-153. [Presented at the Yearly Meeting of the Society of the German Paychiatrist, in Munich, directed by Dr. J Raecke] [Retrieved from: https://www.karger.com/Article/Pdf/220780]
https://www.karger.com/Article/Pdf/22078... Other cases, however, exhibited a progressive course, finally reaching a marked degree of dementia, with serious manifestations of senile mental impairment (Alterblödsinn).⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85...

In the same paper, Alzheimer cited Noetzli, who following Forel's opinion, expressed that the silent form of Senile dementia might affect everyone, possibly more so those predisposed to atheromatous disease, whereas individuals with more advanced manifestations accompanying age related-mental impairment required a psychic hereditary load, in agreement with some authors that held the opinion that a 2^nd item must be added to elucidate the process.¹⁴14. Windscheid F. Die Beziehungen der Arteriosklerose zur Erkrankungn des Gehirns. Münchn Med Wochenschrift 1902;49(9):345-347. [Conference held at the Medical Association of Leipzig, in 1901][Retrievedd from: This view, despite its tempting appeal, seemed barely demonstrable to Alzheimer.⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... Later, Noetzli himself referred to atheromatous degeneration as the fundamental cause of Senile dementia, contradicting his former belief and in agreement with Alzheimer's previous opinion.⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... Thus, at the time, most researchers agreed that atheromatous degeneration of the brain vessels was the underlying mechanism of Senile dementia.

Alzheimer, however, reconsidered this position after examining a case classified as presenile dementia featuring severe atrophy of [cortical] ganglion cells [nerve cells, neurons], but with negligible atheromatous vessel changes. The case, at least for this form, contradicted Noetzli's latest views, and prompted Alzheimer to consider the possibility that a hereditary load might lead to precocious atrophy of the nerve cells independently of vessel disease. These results encouraged him to propose that degenerative changes of the nerve cells might also appear, independently of a vascular disease, in cases of typical Senile dementia. Therefore, an influence of psychic hereditary load on the cause of Senile dementia would make more sense. However, he concluded that a single case could not be considered final proof, and further investigation was needed to support this assumption.⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... ^, ¹¹11. Alzheimer A. Die arteriosklerotische Atrophie des Gehirns. Neurol Centralblatt 1894;13:765-767.

It is pertinent to summarize Jean Noetzli's and Alfred Campbell's data on brain weight, and Campbell pathological analysis for a better understanding of brain pathology of insane patients. Noetzli, Forel's adherent, in his inaugural dissertation Ueber Dementia Senilis (On Senile dementia),¹⁴14. Windscheid F. Die Beziehungen der Arteriosklerose zur Erkrankungn des Gehirns. Münchn Med Wochenschrift 1902;49(9):345-347. [Conference held at the Medical Association of Leipzig, in 1901][Retrievedd from: described a clinicopathological analysis of 70 cases mostly dissected by Forel himself. He provided data on the brain weight of 40 selected cases of "senile psychosis without focal symptoms", which displayed a significant loss of brain weight [brain atrophy] in both genders, compared to controls.⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... ^, ¹⁴14. Windscheid F. Die Beziehungen der Arteriosklerose zur Erkrankungn des Gehirns. Münchn Med Wochenschrift 1902;49(9):345-347. [Conference held at the Medical Association of Leipzig, in 1901][Retrievedd from: Along the same lines, Campbell detected brain atrophy among males and females, in a comprehensive study of the nervous system of 50 patients that he called "aged insane".¹⁵15. http://www.bium.univ-paris5.fr/histmed/medica/cote?epo0561]
http://www.bium.univ-paris5.fr/histmed/m... Campbell also provided detailed gross and microscopic description of the material. Alzheimer apparently considered "aged insane" and Senile dementia equivalent, transcribing part of Campbell's text in his 1898 paper⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... (Box 1).

Box 1.
Excerpts on the neuropathology of Senile dementia, based on Campbell's paper.6,15

Alzheimer also acknowledged that: "Besides the typical Senile dementia, where diffuse changes in cerebral cortex are found, it was still possible to distinguish among the senile psychosis, various disease forms (subforms), well-characterized clinically and histologically, having arteriosclerotic degeneration of brain vessels in common as the underlying cause, and equally observed in the aged. Many of these subforms, depending on the base disease, can resemble the clinical picture of Senile dementia". He affirmed that some of these conditions are to be considered as mere subforms of Arteriosklerotische Hirnatrophie (Arteriosclerotic atrophy of the brain).⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... ^, ¹⁶16. Meyer A. Ueber Dementia Senilis by Jean Noetzli. Psychological Review 1896; 3(2):224-226. [Retrieved from: https://ia600302.us.archive.org/29/items/psychologicalre02assogoog/psychologicalre02assogoog.pdf]
https://ia600302.us.archive.org/29/items... The subforms he mentioned will be addressed later.

Concluding, Alzheimer stated that: "Regarding Senile dementia, it is necessary to see with reservation whether arteriosclerosis of the brain vessels should be considered as the only underlying cause of senile degeneration of the brain, or whether primary atrophic processes of ganglion cells should also be taken into consideration. In the remaining disease forms, atheromatous vessel degeneration is clearly a central factor in the degenerative process."⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... ^, ¹¹11. Alzheimer A. Die arteriosklerotische Atrophie des Gehirns. Neurol Centralblatt 1894;13:765-767.

COMMENTARIES

Based on his own observations, in addition to work by Weigert, Noetzli and Campbell , Alzheimer was a pioneer in conceptualizing Senile dementia as a disorder featuring diffuse changes of the cerebral cortex and subcortical structures, and distinct from syphilitic disease, one of his objectives.⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... ^, ¹⁵15. http://www.bium.univ-paris5.fr/histmed/medica/cote?epo0561]
http://www.bium.univ-paris5.fr/histmed/m...

Alzheimer extricated from the group of "senile psychosis", many of them at the time included under the umbrella-label of Senile dementia, two subtypes of disorders,⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... ^, ¹¹11. Alzheimer A. Die arteriosklerotische Atrophie des Gehirns. Neurol Centralblatt 1894;13:765-767. which can be denoted as an "arteriosclerotic subtype" (Box 2) and a "neurodegenerative subtype" (Box 3).

Box 2.
The "arteriosclerotic subtype" of Senile dementia.

Box 3.
The "neurodegenerative subtype" of Senile dementia.

Additionally, Alzheimer, as did Weigert, Noetzli, and Windscheid, provided insights on the relationship between neuropathological and clinical severity. Milder pathology was associated with lesser cognitive decline. However, he added, the disease could worsen leading to the mild or "silent form" of Senile dementia and even progress to a severe dementia state, accompanied eventually by several kinds of behavioral disturbances.⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85...

The "arteriosclerotic subtype" of Senile dementia (Box 2) and the several grades of clinicopathological presentations he described, also quoting other colleagues, might be considered comparable to the current dimensional concept of the "Vascular cognitive impairment" continuum.¹⁸18. Alzheimer A. Beitrag zur pathologischen Anatomie der Seelenstoerungen des Greisenalters. Neurologisches Centralblatt 1899;18:95-96. It is opportune to reiterate that this was verified and suggested in relation to Arteriosclerotic atrophy of the brain in a previous paper.³3. Leipzig: Barth, 1910, pp 627-628. [Retrieved from: http://www2.biusante.parisdescartes.fr/livanc/index.las?cote=63261x02&do=chapitre]
http://www2.biusante.parisdescartes.fr/l... An analyzes of Senile dementia based on Alzheimer's 1898 paper was performed by Förstl and Howard, where they commented on the clinical progression of Senile dementia etiopathogenesis according to Noetzli and Alzheimer, and on Arteriosclerotic brain atrophy.¹⁹19. Derouesné C. La maladie d'Alzheimer: regards sur le présent à la lumière du passé. Une approche historique. Psychol NeuroPsychiatr Vieil 2008;6:115-128. In 1999, Román commented on Senile dementia, focusing on the main points of Alzheimer's study, and made remarks on Arteriosclerotic brain atrophy and also on some subforms.⁷7. Alzheimer A. Neuere Arbeiten über die Dementia senilis und die auf atheromatöser Gefässerkrankung basierenden Hirnkrankheiten. Monatsschr Psychiat Neurol 1898;3:101-115.

The "neurodegenerative subtype" of Senile dementia (Box 3) was based upon severe primary atrophy of [cortical] ganglion cells [nerve cells, neurons], with insignificant atheromatous vascular changes, found in the material of a presenile dementia case.⁶6. Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
http://gallica.bnf.fr/ark:/12148/bpt6k85... ^, ²⁰20. Hachinski V. Vascular dementia: a radical redefinition. Dementia 1994; 5:130-132. He extended this possibility to senile cases, an issue confirmed later by Oscar Fischer's studies.²²22. Engelhardt E, Gomes MM. Alzheimer's 100th anniversary of death and his contribution to a better understanding of Senile dementia. Arq Neuropsiquiatr 2015;73:159-162. Román,⁷7. Alzheimer A. Neuere Arbeiten über die Dementia senilis und die auf atheromatöser Gefässerkrankung basierenden Hirnkrankheiten. Monatsschr Psychiat Neurol 1898;3:101-115. as well as Derouesné,¹⁷17. Campbell AW. The morbid changes in the cerebro-spinal nervous system of the aged insane. J Ment Sci 1894;40: 638-649. [Retrieved from:http://www.evolve360.co.uk/Data/10/RainhillDaysFinalText.pdf]
http://www.evolve360.co.uk/Data/10/Rainh... also commented on this possibility.

CONCLUSION

Alzheimer was able to distinguish Senile dementia from syphilitic brain disease. Additionally, he discriminated two clinicopathological subtypes, an "arteriosclerotic subtype", possibly related to "Vascular cognitive impairment", and a "neurodegenerative subtype", characterized by primary [cortical] nerve cell degeneration, in a presenile dementia case, possibly foreshadowing a disease he described years later that would carry his name, "Alzheimer' disease". He extended the latter possibility to also encompass senile cases, confirmed later by Fischer's studies.

Acknowledgements.

The authors are grateful to Mrs. Melanie Scholz, librarian, Institute for History of Medicine, Charite, Berlin, Germany, for kindly supplying the digitalized versions of Alzheimer's publications on vascular diseases of the brain.

REFERENCES

¹
Alzheimer A. Uber eine eigenartige Erkrankung derHirnrinde. Allg Z Psychiat phychish-gerichtliche Medizin1907;64:146-148.
²
Kraepelin E. Psychiatrie: ein Lehrbuch für Studierende und Ärzte. Vol II.
³
Leipzig: Barth, 1910, pp 627-628. [Retrieved 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
⁴
Engelhardt and Grinberg LT. Alzheimer and vascular brain disease: the Arteriosclerotic atrophy of the brain. Dement Neuropsychol 2015;9:81-84.
⁵
Boller F, Forbes MM. History of dementia and dementia in history: an overview. J Neurol Sci 1998;158:125-133.
⁶
Esquirol JED. Des maladies mentales: considérées sous les rapports médical, hygiénique et médico-légal. [Vol 2] Paris:JB Baillière, 1838. [Retrived from: http://gallica.bnf.fr/ark:/12148/bpt6k85089d]
» http://gallica.bnf.fr/ark:/12148/bpt6k85089d
⁷
Alzheimer A. Neuere Arbeiten über die Dementia senilis und die auf atheromatöser Gefässerkrankung basierenden Hirnkrankheiten. Monatsschr Psychiat Neurol 1898;3:101-115.
⁸
Román GC. A historical review of the concept of vascular dementia: lessons from the past for the future. Alzheimer Dis Assoc Disord 1999; 13(Suppl 3):S4-S8.
⁹
Berchtold NC, Cotman CW. Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s. Neurobiol Aging 1998;19:173-189.
¹⁰
Berrios GE. A Conceptual History in the Nineteenth Century. In: Principles and Practice of Geriatric Psychiatry. 3rd ed. Abou-Saleh MT,Katona CLE, Kumar A eds. Chichester: John Wiley& Sons, 2011, pp 3-6.
¹¹
Alzheimer A. Die arteriosklerotische Atrophie des Gehirns. Neurol Centralblatt 1894;13:765-767.
¹²
Alzheimer A. Die Seelenstörungen auf arteriosklerotischer Grundlage. Allg Z Psychiat 1902;59:695-710.
¹³
Alzheimer A. Die Seelenstörungen auf arteriosklerotischer Grundlage. Monatsschrift für Psychiat Neurol 1902;12:152-153. [Presented at the Yearly Meeting of the Society of the German Paychiatrist, in Munich, directed by Dr. J Raecke] [Retrieved from: https://www.karger.com/Article/Pdf/220780]
» https://www.karger.com/Article/Pdf/220780
¹⁴
Windscheid F. Die Beziehungen der Arteriosklerose zur Erkrankungn des Gehirns. Münchn Med Wochenschrift 1902;49(9):345-347. [Conference held at the Medical Association of Leipzig, in 1901][Retrievedd from:
¹⁵
http://www.bium.univ-paris5.fr/histmed/medica/cote?epo0561]
» http://www.bium.univ-paris5.fr/histmed/medica/cote?epo0561
¹⁶
Meyer A. Ueber Dementia Senilis by Jean Noetzli. Psychological Review 1896; 3(2):224-226. [Retrieved from: https://ia600302.us.archive.org/29/items/psychologicalre02assogoog/psychologicalre02assogoog.pdf]
» https://ia600302.us.archive.org/29/items/psychologicalre02assogoog/psychologicalre02assogoog.pdf
¹⁷
Campbell AW. The morbid changes in the cerebro-spinal nervous system of the aged insane. J Ment Sci 1894;40: 638-649. [Retrieved from:http://www.evolve360.co.uk/Data/10/RainhillDaysFinalText.pdf]
» http://www.evolve360.co.uk/Data/10/RainhillDaysFinalText.pdf
¹⁸
Alzheimer A. Beitrag zur pathologischen Anatomie der Seelenstoerungen des Greisenalters. Neurologisches Centralblatt 1899;18:95-96.
¹⁹
Derouesné C. La maladie d'Alzheimer: regards sur le présent à la lumière du passé. Une approche historique. Psychol NeuroPsychiatr Vieil 2008;6:115-128.
²⁰
Hachinski V. Vascular dementia: a radical redefinition. Dementia 1994; 5:130-132.
²¹
Förstl H, Howard R. Recent Studies on Dementia Senilis and Brain Disorders Caused by Atheromatous Vascular Disease: By A. Alzheimer, 1898. Alz Dis Ass Disord 1991;5:257-264.
²²
Engelhardt E, Gomes MM. Alzheimer's 100th anniversary of death and his contribution to a better understanding of Senile dementia. Arq Neuropsiquiatr 2015;73:159-162.
²³
Fischer O. Miliare Nekrosen mit drusigenWucherungen der Neurofibrillen, eine regelmässige Veränderung der Hirnrinde bei seniler Demenz. Monatsschr Psychiat Neurol 1907;22:361-372.
²⁴
Fischer O. Die presbyophrene Demenz, deren anatomische Grundlage und klinische Abgrenzung. Z Ges Neurol Psychiat 1910;3:371-471.

Support. Lea T. Grinberg is supported by NIH grant R01AG 040311 and institutional grants by NIH grants P50AG023501, P01AG019724.

Publication Dates

Publication in this collection
Apr-Jun 2015

History

Received
20 Jan 2015
Accepted
27 Mar 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

[1] ¹
Alzheimer A. Uber eine eigenartige Erkrankung derHirnrinde. Allg Z Psychiat phychish-gerichtliche Medizin1907;64:146-148.

[2] ²
Kraepelin E. Psychiatrie: ein Lehrbuch für Studierende und Ärzte. Vol II.

[3] ³
Leipzig: Barth, 1910, pp 627-628. [Retrieved 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

[4] ⁴
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