How did the eponym Alzheimers disease come into being

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In the autumn of 1903, Alois Alzheimer left Frankfurt. Following a short stay in Heidelberg, he moved to Munich to continue his scientific and medical activities at the Royal Psychiatric Clinic under director Emil Kraepelin. After Auguste D. died on April 8, 1906, Alzheimer asked that the record and the brain be sent to Munich. He immediately did a report on the admission formulas used in Munich at this time and wrote a full-page epicrisis. After this he made an entry to the autopsy book of the clinic under the number 181, dated 28 April 1906, Frankfurt, followed by the last name "D." and the source of the tissue as Frankfurt (Graeber et al. 1998). This proves that the brain had been analyzed in his famous neuropathologic laboratory. Within six months, on November 3,1906, he presented his findings at the thirty-seventh meeting of the Southwest German Psychiatrists in Tübingen. In 1907 the lecture was published in Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin under the title, "A Characteristic Serious Disease of the Cerebral Cortex."

In this paper, Alzheimer described Auguste D.'s disease as follows:

The patient showed early clinical symptoms that deviated from the common ones and could not be classified under any well-known clinical patterns. The anatomical findings were also different from those of the usual disease processes. This disease started with a strong feeling of jealousy toward her husband. Very soon she showed rapidly increasing memory impairments She was disoriented as to time and place. Within half a year, Auguste developed symptoms typical for presenile dementia, later called Alzheimer's disease. Her neurological status was normal. There were no motoric disturbances in her gait or use of her hands. Her pupils reacted normally. ... After four-and-a-half years of illness, the patient died. She was completely apathetic in the end and was confined to bed in a fetal position (with legs drawn up), was incontinent, and in spite of all the care and attention given to her, she suffered from decubitus. The autopsy showed an evenly affected atrophic brain without macroscopic foci. The larger cerebral vessels showed arteriosclerotic changes.

Concerning histopathology, Alzheimer wrote:

The Bielschowsky silver preparation showed very characteristic changes in the neurofibrils. However, inside an apparently normal-looking cell, one or more single fibers could be observed that became prominent through their striking thickness and specific impregnability. At a more advanced stage, many fibrils, arranged parallel, showed the same changes. Then they accumulated, forming dense bundles, and gradually advanced to the surface of the cell. Eventually the nucleus and cytoplasm disappeared, and only a tangled bundle of fibrils indicated the site where once the neuron hadbeen located. As these fibrils can be stained with dyes different from the normal neurofibrils, a chemical transformation of the fibril substance must have taken place. This might be the reason why the fibrils survived the destruction of the cell. It seems that the transformation of the fibrils goes hand in hand with the storage of an as yet not closely examined pathological product of the metabolism in the neuron. About one-quarter to one-third of all the neurons of the cerebral cortex showed such alterations. Numerous neurons, especially in the upper cell layers, had totally disappeared.

Dispersed over the entire cortex, and in large numbers, especially in the upper layers, miliary foci could be found, which represented the sites of deposition of a peculiar substance in the cerebral cortex. It was even possible to recognize these without staining, but they were much more evident once stained.

The glia had abundant formed fibers; in addition, many glia cells showed large deposits. There was no infiltration of the vessels. Against this, focal lesions in the endothelium could be observed, and in some sites new vessel formation could also be seen (Fig. 10).

Alzheimer concluded:

On the whole, it is evident that we are dealing with a peculiar, little-known disease process. In recent years these particular disease processes have been detected in great numbers. This fact should stimulate us to further study and analysis of this particular disease. We must not be satisfied to force it into the existing group of well-known disease patterns. It is clear that there exist many more mental diseases than our textbooks indicate. In many such cases, a further histological examination must be done to determine the characteristics of each single case. We must reach the stage in which the vast, well-known disease groups must be subdivided into many smaller groups, each one with its own clinical and anatomical characteristics.

We learn more about Alzheimer's 51-year-old female patient in a 1909 article written by E. Perusini, "On Histological and Clinical Findings of Some Psychiatrie Diseases of Older People." On the Suggestion of Alzheimer, Perusini "examined four cases all characterizedby clinical and especially anatomopathological signs." In this publication, Alzheimer's patient (case 1) was investigated again concerning her symptoms and histopathology. The initials of the surname, the complete Christian name, and the profession of her husband were mentioned for the first time ("D. Auguste, wife of an office clerk, aged 51 1/2 years"). Perusini and Alzheimer thanked Dr. Sioli in Frankfurt for the use of the case history and the brain for microscopic research. These facts prove that Perusini's case l was identical to the case described by Alzheimer in 1907.

Concerning Auguste D.'s plaques, Perusini stated, "In preparations for myelin sheath, clear yellow-grey or yellow spots of different sizes are seen between the darkly colored fibers. It is difficult to count the number of those plaques. Many are seen in the preparations that show plaques." In another part of the paper, Bielschowsky's method is mentioned and described as "especially favorable for showing such tonnation; by this method the plaques are seen impregnated more or less intensely with silver nitrate". Concerning neurofibrils, Perusini stated that "some cells are recognized only by their fibrillar skeletons: between the single fibrils that are clearly present there exists a particular myelin substance; this is colored metachromatically with toluidine blue".

Perusini concluded that "the pathological process recalls the main features of senile dementia. However, the alterations in the cases described are more far-reaching, although some of them represent presenile diseases. Regarding the clinical symptoms, those cases are peculiar as well. Apart from varying affective anomalies and varying psychotic symptoms, serious amnesia and rapid weakness of intelligence are present very early in the course of this disease."

Besides the two essential publications of Alzheimer (1907a) and Perusini (1909), Kraepelin must have been familiär with the publications of Bonfiglio and Sarteschi. In 1908 Bonfiglio reported in Italian on the initiative of Alzheimer. Bonfiglio's 60-year-old patient exhibited similar symptoms and histopathologic findings. Sarteschi also published cases in Italian.

In the eighth edition of his Handbook of Psychiatry (1910), Kraepelin completely reorganized the chapter on senile dementia (Fig. 11). Kraepelin mentioned Alzheimer dis-

Auguste Neurofibrils

Fig. 10. (a) Neurofibrils of Auguste D. (b) Pictures drawn with Abbe's camara lucida. Under 2 and 3 plaques of Auguste D.

Fig. 10. (a) Neurofibrils of Auguste D. (b) Pictures drawn with Abbe's camara lucida. Under 2 and 3 plaques of Auguste D.

PSYCHIATRIE

EIN LEHRBUCH FÜR STUDIERENDE UND ÄRZTE

DR. EMIL KRAEPELIN

AN Dt H UNIVERSITÄR MÜNCHEN ACHTE, VOLLSTÄNDIG UMGEARBEITETE AUFLAGE

II. BAND KLINISCHE PSYCHIATRIE I. TEIL

MIT 151 ABBILDUNGEN UND 27 SCHRIFTPROBEN

LEIPZIG

VERLAG VON JOHANN AMBROSIUS EARTH 1910

Fig. 11. Front page of Kraepelin's textbook ease for the first time in the following text: The clinical interpretation of this Alzheimer's disease is still confusing. While the anatomical findings suggest that we are dealing with a particularly serious form of senile dementia, the fact is that this disease sometimes starts as early as the late 40s. In such cases we should at least assume a "senium praecox," if not rather a more or less age-independent peculiar disease process. The clinical picture involving an extraordinarily serious dementia, serious speech disorder, spastic signs, and seizures differs distinctively from "presbyophrenia," because pure senile cortical changes accompany this disease. Perhaps relations with one or more presenile diseases exist. (Kraepelin 1910)

In introducing the eponym Alzheimer's disease, Kraepelin likely knew only the few cases in table 1 (Fig. 12). This was confirmed by Alzheimer himself in his 1911 paper, "Über eigenartige Krankheitsfälle des späteren Alters," pointing only to his own 1907 publication and those of Bonfiglio (1908) and Perusini (1909). One case from Sarteschi (1909), describing a 67-year-old female, does not fit into the scheme.

It is of some interest that Alzheimer's case of Auguste D. is, in fact, Perusini's case 1. Some features have been changed (i.e., the postmortem results no longer showed arteriosclerosis). Besides that, the Perusini paper described Auguste D.'s histopathologic peculiarities in detail, with numerous plaques showing pictures drawn with Abbe's camera lucida or photographs with Zeiss plana. Likewise, Perusini's fourth case (Leonhard Sch.) was the same as that described by Bonfiglio (1908).

Thus, Kraepelin had knowledge of only four cases (Auguste D., Leonhard Seh., R.M. male, and BA female) and knew their histopathologic findings.

The second case published by Alzheimer in 1911 involved Johann F., who had been admitted to the hospital on November 12, 1907, and died on October 3, 1910. Certainly Kraepelin knew him from his ward rounds and was familiar with his history and clinical signs. However, it is unlikely that he knew the histopathologic findings of Johann F. when he was writing the eighth edition of his textbook and defining the term "Alzheimer's disease."

Why did Kraepelin, who introduced the eponym Alzheimer disease, use Alzheimer's name and not that of Perusini or Bonfiglio? Alzheimer was the editor of the Journal in which Perusini published his 1909 paper, which starts as follows: "On the Suggestion of Dr. Alzheimer, I examined the following four cases characterized by clinical and especially anatomo-pathological signs in common." Of interest is the fact that most of the papers in the series, Histologicel und histopathologische Arbeiten über die Großhirnrinde (Histological and Histopathological Studies on the Cerebral Cortex), edited by Nissl and Alzheimer, had single authors. Thus, according to modern convention, Alzheimer was the senior author of the publication in which Perusini described the four cases. It was also common at this time for the editor of such an important Journal to stay in the background.

Case

Author / Year of Publication

AgeCyr.)

Auguste D.

Alzheimer, 1907

51

Leonard Sell.

Bonfiglio, 1908

60

AugnsteD.

Penisini, 1909

51

R.M.

Penisini, 1909

45

B.A.

Penisini, 1909

65

Leonard Sch.

Penisini, 1909

60

Fig. 12. Table 1: Published cases of AD available to Kraepelin in 1910

Fig. 12. Table 1: Published cases of AD available to Kraepelin in 1910

Fig. 13. Histological examination of Auguste D.'s brain, showing neurofibrillary tangles and amyloid plaques

Of the four cases (Auguste D., Leonhard Seh., R.M., and B.A.) that had been verified histopathologically at the time the eponym was created, that of Auguste D. was the most prominent. Since that early start in 1907, the Auguste D. case has been cited numerous times and was used for introductions to publications and articles covering the field of AD. We are convinced that the eponym Alzheimer disease was based mainly on Alzheimer's 1907 report of Auguste D. and the few cases published by Perusini.

Several hypotheses have been suggested to account for the haste with which Krae-pelin created the eponym. Beach (1987) says that Kraepelin did so for scientific reasons (i.e., because he believed that Alzheimer had discovered a new disease). Another reason might have been the existing rivalry between Kraepelin's department and that of Pick in Prague and Kraepelin's desire for prestige for his Munich laboratory. Also plausible is Kraepelin's wish to show the superiority of his school over psychoanalytical theories and to show (vis-a-vis Freud) that some mental disorders were organically based. The most likely explanation, however, is the close collaboration that existed between Kraepelin and Alzheimer, and Kraepelin's awareness of Alzheimer's clinical and scientific work on presenile cases.

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