Hans Förstl


Alois Alzheimer: 

Über eigenartige Krankheitsfälle des späteren Alters (1912)

(On certain peculiar diseases of old age) 

With 10 Text figures and 2 Plates
(Received 11 January 1911)

 In 1906 I described a case of disease of the presenium which during life presented features different from those of recognized diseases and which on microscopic examination showed alterations of the cerebral cortex that were then unknown. The most notable clinical feature was that of a rapidly developing mental impairment which progressed rapidly to the most severe degree. From the start, various focal symptoms, mostly of an aphasic and asymbolic kind, were noticeable. As there were no other symptoms pointing to a focal disease, no suggestion of paralytic, luetic or arteriosclerotic disease, and because senile dementia was out of the question since the patient was only 56 years of age and the clinical picture unlike that of this condition, this case could not be categorized among known disorders.

The microscopy of Bielschowsky-stained tissue showed a strikingly peculiar degeneration of cortical nerve-cells which was essentially characterized by a clotting of fibrils which changed their staining-properties and outlived the cellular disintegration so that in the end there were bundles of fibrils lying in the tissue rolled up 1ike coils or twisted 1ike slings as the only remnants of the cell. In addition there were an extraordinary number of peculiar patches disseminated throughout the whole cortex.

In almost all of the succeeding years new examples of simi1ar cases were reported. In 1908 BONFIGLI0 described one, in 1909 PERUSINI presented a clinical and anatomical description of  4 cases. Since then 2 new cases have been seen here and examined anatomically. In the 8th edition of his Psychiatry, KRAEPELIN produced a summarized account of this disease which he called Alzheimer's disease.

The patches in the cortex had in the meantime been observed in presbyophrenia by FISCHER who described them in detail in a number of papers and considered them as a characteristic feature of that disorder. REDLICH had also demonstrated them by different methods. I had myself already observed and described them in Dementia senilis using Nissl and Weigert staining. I had not however realized that they corresponded to the images seen in Bielschowsky-stained preparations. PERUSINI has pointed out that the fibrillary changes in nerve cells which I had described are also seen in severe cases of Dementia senilis and FISCHER has expressed the same view. The question therefore arises as to whether the cases of disease which I considered peculiar are sufficiently different clinically or histologically to be distinguished from senile dementia or whether they should be included under that rubric.

PERUSINI felt that these cases represented a separate disease, partly for clinical and partly for histological reasons. The clinical differences were the early onset, and the presence and severity of focal symptoms which were not thought to be a feature of Dementia senilis, the anatomical differences being the greater severity of the histological changes although they develop at an earlier age. KRAEPELIN still considers that the position of these cases is unclear. Even if the anatomical findings might suggest severe mental impairment, the early onset (one would have to assume a 'senium praecox'), the profound language disturbance, spasticity and seizures are very different from those of presbyophrenia which is usually associated with purely cortical senile changes. The disease may therefore be related to one or to the other of the pre-senile conditions which he described. FISCHER has written an exhaustive discussion of PERUSINI'S cases in his paper 'The presbyophrenic dementia, its anatomical basis and clinical differentiation'. He considered the patches as characteristic of a specific disorder and saw no objections 10 including in the same category cases occurring at an early age, both because of the histological changes and because the paralysis of adults and young people which represent the disease at a different age share all the essential features of later cases.

It seems to me that a simple inclusion of these cases with presbyophrenia does not take sufficient account of several interesting features, and that PERUSINI'S and KRAEPELIN'S reservations against this integration have not been convincingly eliminated by FISCHER'S arguments. After all, we are dealing with the case of a 56-year-old woman and of PERUSINI'S 46-year-old man, in whom nobody would have made a clinical diagnosis of senile dementia. Whereas general paralysis shows similar features whether it occurs in the young or the middle-aged, the symptoms in our cases are remarkably different from simple presbyophrenia. The clinical picture of presbyophrenia provides a poor starting point for attempting to recognize these disorders during life and for distinguishing them from others. We will have to use a different clinical definition from that currently employed. With regard to the paralysis of adults and young people we know that the clinical picture is determined by the age of onset. Should we ever come to the conclusion that severe senile cortical changes may occur in the forties this would represent an important advance in knowledge. This would also provide a guide to the classification of so me psychoses of late life which are still nosologically unclear. However, it would still not explain why these cases differ from simple senile dementia and have such severe symptoms. In the light of new observations, there are therefore good reasons to discuss in some detail the clinical and histological characteristics of these cases and their relations hip to other diseases and especially to Dementia senilis. I would like to begin by presenting one of the patients seen here recently as it illustrates some of the difficulties of making a clinical judgement about these cases.

The 56-year-old labourer Johann F. was admitted to the psychiatric Clinic on 12 Nov. 1907. There was no history of excessive drinking. Two years before admission his wife died, since when he became quiet and dull. In the previous 6 months he had become forgetful, could not find his way, could not perform simple tasks or carried these out with difficulty. He stood around, did not appear to bother about food, but ate greedily whatever was put before him. He was not capable of buying anything for himself and did not wash. He was admitted by the service for the poor.

14 Nov. 1907. Pupillary reaction normal. Patellar-reflex a little brisk. No signs of nervous palsy. Language strikingly slow, but without articulatory disturbance. Dull, slightly euphoric, impaired understanding. Echoes questions put to him frequently and repeatedly instead of giving a reply. Can only solve very simple calculations after a long delay. When asked to point to different parts of his body, he hesitates. After having spoken about the knee-cap, he calls a key a knee-cap. Does the same with a matchbox, which he rubs against his knee-cap when asked what one would do with it. He then does the same with a piece of soap. He finally responds correctly to other commands to unlock a door or to wash his hands but only does so extraordinarily slowly and clumsily.

20 Sept. 1907. To the question, what is the colour of blood? 'red'; snow? 'white'; milk? good; soot? Counts correctly to 10, does the same with days of the week and months of the year. Gives half of the 'Our father' but cannot continue. 2 x 2 = 4, 2 x 3 = 6, 6 x 6 = 6. Reads the time correctly. Unbuttons his frock correctly. Takes a cigar in his mouth, strikes a match, lights the cigar and smokes: everything in the correct manner. Takes coins in his hands and checks each side. 'That is, that is, we have got a, here, here, . . .' Similarly, he cannot name a matchbox. He knows how to use a mouth organ, bell, purse, but cannot name them. When asked to do so, he selects a matchbox and a light from a number of objects but not a brush or a corkscrew. When asked to bend his knees, he makes a fist. Repetition is unimpaired. How many legs has a calf? '4'. A man? '2'. Where does a fish live? In the forest up on the trees? 'In the forest up on the trees.' Lumbar puncture: No increased cell count. No alteration in complement in blood and cerebrospinal fluid. Ophthalmoscopy: blurring of the right papilla, veins weIl filled, normal findings on the left.

23 Sept. 1907. Gets up and urinates by the bed.

8 Oct. 1907. When asked to write, he does not take the pencil but picks a matchbox and tried to write with it. Otherwise focal symptoms show striking changes in severity.

15 Nov. 1907. Happy, laughs a lot, eats an extraordinary amount. Sits around looking dull but moves his hands constantly, picking his blanket or his shirt. At times he tears pieces of cloth which he pushes into his mouth. Repitition still good. He often uses objects in the wrong way, e.g. tries to brush his frock with his combo When he is given a key and is asked to unlock the door, he approaches the door but does not know what to do. When writing his name he sticks to letters. He cannot be persuaded to write anything but his name. When he is asked to name objects, he does not respond promptly, or echoes the question without understanding it, at times repeatedly. He does not speak spontaneously. When teased, e.g. by trying to take away a cloth, which he is uncoiling, he sometimes curses. When asked to carry out a movement, he often repeats the question. When the movement is demonstrated to him, he usually looks without appearing to understand. He imitates some of the demonstrated movements with his right or left hand. When asked to touch his nose with his right hand, he holds the extended fingers to his chin. When asked to blow a kiss, he holds out his hand in a peculiar way. Then when a threatening gesture and a military salute are demonstrated to him, he puts his hand to his mouth as though blowing a kiss.

8 Dec. 1907. Obviously further deterioration. Keeps leaving his bed, fusses around with his sheets. Wassermann's test in blood and serum negative. 1 cell per mm3 cerebrospinal fluid.

2 March 1908. Asked to wash his hands, he starts correctly but then keeps on washing endlessly. Asked to close a tap, he holds his hands under it. Asked to seal a letter, he tries to light the candle with the seal, then he warms up the sealing-wax and applies it against the seal. Asked to light a cigar, he strikes it against the matchbox.

4 March 1908. Restless, appears as though delirious. Keeps rolling his sheets into a bundle and wants to walk out with them. He often keeps working away for days on end without a break, his face sweating. Gets more and more reluctant. Does not obey when summoned. When given a hairbrush, he licks it. Almost no spontaneous speech.

5 May 1908. Other patients have taught him how to sing. When asked he sings: 'We sit so happily together'. He has to be prompted again and again with the words but does rather well with the tune.

12 May 1908. Physical examination does not yield any abnormal results in either of the pupils or the reflexes. Papillae look normal (right papilla shows a slightly abnormal configuration). When asked for something, he usually answers with a 'yes' and laughs idiotically, or repeats the question without understanding. He is still quite capable of repetition and at times he keeps repeating the word several times. He generally imitates individual movements, like extension ofhands, swearing correctly, but clumsily.

12 June 1908. He walks in the garden and will not let anyone stop him. Although completely soaked with sweat, he walks round and round continuously, constantly winding the long coat-tails of his frock round his hand which he clenches occasionally. In his bed he does the same thing with his blanket. When pricked with a needle or tickled on his soles, he does not react for a long time but finally hits the physician. Hardly utters a word. It is striking that his gross motility appears unimpaired in spite of his profound imbecility. No ataxia or weakness of limb movements are to be seen.

14 Dec. 1908. Incontinent of faeces and urine wherever he is. Does not say anything anymore; is permanently occupied with his bed or shirt. Does still sing 'We are sitting so happily together' when others start him off.

3 Feb. 1909. Epileptiform seizure lasting a few minutes. Twitching of his face.

6 Feb. 1909. Right-sided facial palsy.

9 Feb. 1909. No obvious facial weakness anymore. Repeat tests of blood and serum yield the same negative results as before. Very reluctant to co-operate. Always busy with his blanket or shirt. Does not speak anymore; does not obey any commands.

31 May 1910. His body-weight falls slowly and steadily. Still fidgeting with his sheets in the same manner.

28 July 1910. Epileptiform seizure of 2 minutes duration.

1 Sept. 1910. Temperature increased to 38.5 C. Rhonchi over his lung.

3 Oct. 1910. Death with features of pneumonia.

Thus we see a 54-year-old man who slowly and imperceptibly and with no impairment of consciousness or seizures, develops a state of profound mental impairment with prominent agnostic, aphasic, and apractic disturbances. A more accurate analysis of these focal symptoms presents various problems because the impairment of recognition, language comprehension and expression, as well as praxis, the general mental impairment and reluctant behaviour, make the interpretation of individual verbal capacities and acts difficult. It is, however, certain that the language disturbances of the patients have 10 be considered as transcortical aphasias because of the long-preserved ability for repetition. Since there was an early impoverishment of word production which progressed to a complete loss of spontaneous language, we have to assume a mixed motor and sensory aphasia in spite of gross signs of paralysis. Of the apractic disturbances although these were sometimes purely motor, ideational apraxia was more prominent. In contrast to the severe disturbances of language and of praxis, disturbance of motility was slight and the absence of real signs of paralysis of the extremities was striking. In the late stages of the condition and towards the end of his life, repeated epileptic attacks and a transient right-sided facial nerve paralysis occurred. The clinical analysis of this case raises several difficulties. Senile dementia was never considered because of the onset at the age of 54 and the fact that, even on first examination, a profound mental impairment with a hint of aphasic agnostic and apractic disturbances was found. After physical examination had apparently established a right-sided papilledoema, one had to consider a tumour. Because of the lack of other signs of increased intracranial pressure and the profound general mental impairment with multiple localizing signs, one would have to postulate a diffuse tumour invading nervous tissue without occupying much space. Since repeated examination yielded only a slight abnormality of the right papilla which did not progress, this could not be considered as papilloedema and the diagnosis of a tumour was no longer supported. An arteriosclerotic brain disease could be excluded as no specific alterations of the vessels were found. The facts that vertigo and apoplectiform seizures had been completely absent during the first years of the disease and that the profound imbecility as well as the focal symptoms had developed quite gradually and with no sudden change, argue against a pure cerebral arteriosclerosis. The condition could not have been a typical general paralysis. The diagnosis of an atypical Lissauer's paralysis could not, however, be dismissed until the death, largely because of an experience which we had only a few months before. A patient, who had shown quite a similar picture in many respects (profound mental impairment, sensory aphasia, agnosia, and apraxia), and who, just like case F., had no abnormality of complement in either blood or cerebrospinal fluid on repeated examination, had on microscopic examination turned out to have a progressive general paralysis with atypical localization. It was, however, considered as most probable, because of the agnostic, transcortical aphasic and apractic disturbances, which existed together with profound mental impairment, that we were seeing a relatively unknown progressive and widespread severe cortical disorder , perhaps a case similar to the one I had reported earlier. Autopsy revealed only a moderate opacity and thickening of the pia over the convexity of the brain. The brain vessels only showed minor indications of arteriosclerotic degeneration. The gyri of the frontal, parietal and temporal lobes were considerably narrowed on both sides, the sulci enlarged, while the central gyri did not appear particularly atrophic. There were no softened areas in cortex or white matter nor were any other circumscribed alterations to be found anywhere. The rest of the autopsy findings were without importance. Thus although the macroscopic observation of the brain revealed a diffuse atrophic process which has been established as the cause of the disorder, it did not clarify the nature of the underlying process.

Microscopical investigation showed the cortex to be filled in varying degrees of Fischer's plaques. Their number in general corresponded with the macroscopically recognizable amount of brain atrophy. They were numerous in the frontal lobe, scarce in the central gyri, present in enormous numbers in the parietal and partly also in the temporal lobes and again less numerous in the occipital lobe. There were no obvious differences between left and right sides. In the striatum, lentiform nucleus and thalamus they were also present in abundance. Within the cerebellum they occurred abundantly in individual lobuli, while they were completely absent in other large parts of the brain. Single plaques were also visible in the grey matter of the pons and in different nuclei of the medulla oblongata. In the spinal cord I only saw a solitary one in the posterior horn of a slice at the thoracic level.

Among the plaques in the cerebral cortex many were of an extraordinary size, such as I have never seen, even in the cornu ammonis of senile dementia. They often extended through several slices. Some evidently arose from the fusion of smaller ones since they contained several central cores but others had one exceptionally big central core and an uncommonly large halo. Very frequently it was noticeable that the numbers of plaques at the surface and centre of the gyrus was smaller than those at the sides. In places where they were particularly numerous, the plaques were very rarely located in the first cortical layer. They usually started in the region with a sudden increase of glial reticulum at the transition to the first microcellular layer. There were sometimes a few particularly small ones at the very edge of the first to the second layers. They tended to accumulate in the 2nd and 3rd layers, were rarer in deeper layers but were still fairly numerous in the white matter.

I would like to mention some details about the subtle features of the plaques which are of some interest. Their great abundance and exceptional size makes it easy to distinguish various aspects of their composition. If one cuts through the cortex of an exceptionally severely diseased area which has been stained by Weigert's glial impregnation combined with a modification of Mann's staining method and then examines the section under low power (Text fig.l), it is striking that we perceive an extraordinary number of dark spots of globoid, egg-shaped or often of rather irregular shape and varying size. These are often solitary but sometimes, particularly in the upper layers, they are so aggregated that no normal tissue is seen between them any more. In the centre of many of them, a large central body can be recognized. It stands out because of its intense blue staining. In the smaller plaques it mostly appears circular, but under higher magnification it does not appear very clearly delineated. In the larger plaques it is mostly circular, often with somewhat irregular edges. Frequently one fails to see sharp borders but only ragged protrusions fading into the surroundings, or one gets the impression that the central core might fade away at its delicate border and form subtle, radially arranged beams. Generally however, the cores of the plaques stained by this technique are mostly homogeneous structures and no cellular remains can be seen within them. Sometimes they appear to have an irregular fracture line across them but one wonders whether this is not a result of tearing in the course of slicing of the brain. In the cerebral cortex this plaque-core is regularly surrounded by a halo, which is brighter than the core, but darker than the surrounding tissue and which usually has a much larger diameter than the core. Compared to the core it presents a very complicated structure. At first we see within it darker coloured, irregular shaped, homogeneous, lumpy formations of various sizes. These appear as amorphous deposited masses. Furthermore cellular elements can be demonstrated within this halo and these may undoubtedly be interpreted as being glial cells. Sometimes they are large, sometimes small, sometimes they show only a little pale-coloured cytoplasm near the core, sometimes they are filled with greenish-yellowish masses and their nuclei are squeezed to the periphery, as is often seen in granular cells of any origin. More rarely one sees forms of glial cells which one is tempted to describe as amoeboid because of their small nuclei and homogeneously-coloured, lumpish cell bodies. Real fibre-forming glial cells are usually not seen within the halo of a plaque. On the other hand, compared to what is observed in ordinary cases of senile dementia, we see a far larger number of fibre producing glial cells lying in the immediate vicinity of the plaque, sending fibres into the halo but not into the core. They extend between the lumps described above. In rare cases one can also see fibre-producing glial cells sending a protoplasmic protrusion into the halo in addition to several fibres. This protrusion is club-shaped and thickened at its end which contains green-coloured lipoid granules. Sometimes there are also rod-like cell elements of obvious glial origin lying in the halo. At both poles of the core lies a sack filled with greenish granules. Sometimes brighter streaks with straight or jagged bent edges extend through the halo and end at the core of the plaque. Using the staining technique adopted one only occasionally sees an axis cylinder which enters the plaque and ends with a club-like swelling. However, this method, which demonstrates the glial protrusions and axis cylinders quite differently, leaves us in no doubt that axis cylinders may also enter the plaque and undergo alterations there. While one hardly ever sees a plaque-core without a halo, one does come across many such halos without cores. That is not surprising, since in the course of slicing many plaques are only cut across at their margin. However, since one also often sees small irregular darker spots without clear deposits in the cerebral cortex, I believe that the plaques just described must be preceded by a stage-during which the tissue condenses. Unfortunately our methods fail to demonstrate the subtle changes which had taken place. There is no close relationship between the foci and the blood vessels. Sometimes they happen to overlie a vessel and occasionally a vessel may be seen passing through the plaque, but the large majority are clearly well separated from vessels. They even sometimes appear to dislodge capillaries which can occasionally be seen skirting round the plaque.    This demonstration of the plaques by Mann's staining, which demonstrates them extremely clearly, has to be supplemented by other methods.

It is surprising how few appear in Nissl's cell preparation even in those parts of the cortex which are severely affected. In material which has been prepared a few days after the autopsy some but certainly not all the plaques appear as faded, bluish staining spots. The stain is clearly retained only by the plaque core. In preparations which had been submerged in alcohol for a longer time, one sees even fewer of them and that makes it understandable that they should have escaped detection for so long. If one observes toluidine-blue stained slices of the cortex under lower magnification, one can recognize the position of some of the larger plaques in larger areas which are devoid of all cells. Near such areas we often see the nerve cells shifted from their usual position, so the plaque seems to grow from the inside and to dislodge the nervous elements in its vicinity. Under stronger magnification, one can see an accumulation of larger glial cells of the fibre-forming type and single small, granular glial cells abundantly packed with yellowish or greenish coloured deposits, suggesting the presence of a plaque nearby. In this way we can demonstrate the alterations in the cells which are of exceptional interest and to which we will return later. Text fig. 2 shows such a glial cello In the middle we see the faintly coloured core of a plaque and radially pointing towards it, a rod-like glial cell, which sends two cytoplasmatic extensions towards the surface, thereby producing a peculiar fan-shaped appearance surrounding the surface of the plaque. Something very similar is seen in the one glial cell in Text fig. 3, obviously a fibre-forming cell which sends cytoplasmic extensions in all directions but with two exceptionally prominent ones touching the plaque core, over whose surface they spread. The lower cell with its grid-like structure is obviously a small gliogenic granular cello The Nissl-stained preparations are surprising, not only because of the relative invisibility of the plaques but because of the lack of demonstrable disturbance of the cortical architecture and the disruption of nerve cells which appears small in relation to clinical severity. In individual areas one finds a striking deficiency of ganglion cells, most frequently in the third layer. Otherwise the order of the cell elements is not disturbed. When one looks at individual cells, one can see the protrusions including the axis cylinder sticking out and the basophilic substance rather homogeneously dispersed, the whole cytoplasm having a somewhat granular structure. Nowhere in the cells can one see very developed lipid sacks. On the other hand, a rather reticular arrangement of the cell cytoplasm becomes apparent in many places, not only at the basis and in the vicinity of the core, so that one may assume that this represents a deposition of lipoid granules. The core is mostly stained rather dark and merges into the rest of the rather narrow cell form. Especially in the third layer quite a few of the cells appear strikingly pale and seem to be in a state of dissolution, there core granules are only faintly stained. These are cell alterations which are very frequently seen by Nissl staining, especially in the senium. Apart from the pathological glial cell forms in the vicinity of the plaques already mentioned and the small dark glial cores with little differentiated chromatin and very little cytoplasm, elsewhere in the tissue one also often sees glial cells arranged in small accumulations as though forming little glial 'lawns'. These have larger, often oval cores and star-shaped cell bodies, often containing darker spots. Quite regularly larger accumulations of light-refracting granules without clear staining are deposited within these glial cells. Rodlike elements are quite rare. The glial cells in the white matter are greatly increased in number. These include both small and large cells containing shrunken nuclei and little protoplasms among which one can also see larger cells with spider-like dendritic cell bodies.   Next to the vessels one can see nothing but degenerative features. The cores are pyknotic, shrunken, and strikingly pale in colour. Quite an abundant accumulation of uncoloured, yellowish or green products are to be found in the fixed adventitial cells of all vessels, i.e. the granular cells in the adventitial lymphoid-space of the larger vessels in the white matter. A well-developed fibrosis of the vessels is not observed and there is no cell infiltration at all. In addition the larger vessels of the pia show nothing but regressive changes in their cores and no arteriosclerotic alterations. The connective tissues of the glia is increased everywhere, the cores of the fibroblasts being enlarged. In some fibroblasts and in some round-cells, there is an abundance of lipoid products. Next, we see something of interest in the Herxheimer-stained preparations. In slices, which were prepared from formalized material soon after the death (4-8 weeks), the plaques appear quite clearly because their cores are densely sown with great red granules (Plate II, Fig. 1). It is striking that these granules appear much less numerous in older formalized material. They also gradually disappear after a few weeks in glycerol embedded slices so that only a pale bluish hematoxylin-staining plaque-core is seen, while the scarlet-stained granules of the ganglia, glial, and vessel-wall-cells remain their gleaming red. It is difficult to explain this strange phenomenon in any other way but to ass urne that a peculiar lipoid substance has taken up the stain and that this changes faster than the other lipoid substances. In the Bielschowsky preparations something similar can be established. A number of small gliogenic granular cells occur quite regularly in the immediate vicinity of larger plaque-cores. These obviously lie in the halo, that is not clearly defined in these preparations. These cells which retain more dendrites are stuffed with lipid granules, (Plate II, Fig. 1). There are extraordinary rich accumulations of lipid granules in the ganglion cells. In the vast majority the whole cell body is filled with granules up to the upper edge of the nucleus and sometimes these extend into the apical protrusion, the basal protrusions and axis cylinder. Such a complete lipoid degeneration is seen only in senile psychoses. There is an exceptionally high grade of accumulated lipoid substances in the walls of the vessels. Often the adventitial cells packed with lipid granules contrast with those in the vessel wall (Plate I, Fig. 2). In Weigert's glial preparations an enormous increase in fibroid glia is to be seen. At the moment we employ Weigert's method in a somewhat modified form in frozen slices. Using this modification one can demonstrate the subtler glial fibres much better. The following description refers to such preparations. The superficial glial cells are greatly condensed, matted together and their fibres are sturdier than usual. Almost everywhere in the cortex, there are fibre-forming glial cells and in the deeper cortical layers, these form special aggregations. Many remind one of those which are frequently found in Dementia senilis: very numerous bow-shaped, not very thick and not very long fibres form orderly arrangements all round a small chromatin-rich core. Here, however, others form complete bundles containing parallel fibres (Plate I, Fig. 2) and one or more particularly prominent protrusions, clearly filled with cytoplasmatic substance. The latter extend towards the neighbouring vessels, in contrast with which the protrusion expands like a foot and spreads its fibres. This formation of fibroid glia achieves an intensity, which is only seen in progressive paralysis and not as a rule in senile dementia. In the white matter there is also a massive increase of glia. Numerous large astrocytes are interspersed between abundant fibres running along the myelin-sheaths. The relationship of the fibre-glia to the plaques is of exceptional interest. Under low magnifications the plaque-cores are seen to be stained yellowish with chromogen and at the very centre usually take up the brownish-black iodine stain. The halo of the plaque is slightly bluish and under high power this is seen to be due to the presence of an extraordinary number of very delicate glial fibres, spreading in all directions (Plate I, Fig. 1). In the beta-amyloid core of the plaque no part of the fibrils can be seen. A larger number of fibre-forming glial cells is regularly found at the periphery of the halo and most of their longest extensions are directed towards the plaque. One can quite clearly see that some of the fibres, lying in the halo of the plaque, are connected with these cells. The cortex achieves a very striking appearance due to these numerous blue spots which permeate the whole cortical tissue. In the Bielschowsky preparations, plaques are seen in the same frequency, form and order as in the Mann's preparations. The plaque-cores also appear to be covered with black granules of the same size and number as in Herxheimer's preparations and these are more frequent in those made soon after death compared to those produced later. Here again, the halo of the plaque appears clearly and is stained darker than the surroundings and brighter than the core. The darker colour is caused by a light browning of lumpy and granular masses with unclear margins which occupy the whole halo. In between, silver-stained formations of very various kinds stand out. These are partly axis cylinders and cytoplasmic protrusions from neighbouring nerve cells, which traverse the halo, while others skirt around it and partly small, irregularly twisted fibrils, which stain darker than those outside the plaque and in some places are probably more numerous. Finally, there are formations which at first sight remind one of the structure of nerve endings as we know them in muscle or receptor organs. Apart from these very beautifully developed, clearly contoured, and well structured formations, one sees more numerous ones, which are ill-defined, broken-up, condensed or in a state of disintegration. It is often not easy to prove reliably the relationship between these formations and indubitable nerve fibres - unless one holds the obviously erroneous opinion that all the fibres which are stained black in a pathological preparation have to be nerve fibres.

However, I still believe in their nervous origin. Text fig. 4 represents a picture which seems to me to be a proof of this. The nervous fibre, which can be traced much further in the preparation than is reproduced in the drawing and which definitely has to be a nerve fibre, forms several outgrowths in the halo of the plaque or alternatively pursues its course without alteration just as FISCHER has already described. In the same way, it is dearly evident (Textfig. 5) that a fibre forming glial cell lying at the margin of the halo whose fibres are deeply stained, extends to the halo of the plaque, where it widens out rather like the excrescences or outgrowths of the axis-cylinder in Fig. 4. Similar pictures are obtained using a Bielschowsky preparation (Fig. 2) and toluidine-blue preparation (Fig. 3). These show a fan-shaped spreading of the cytoplasmic extensions of a glial cell in the halo of a plaque. The great majority of these multi-faceted blackened formations, however, do not show any relationship to fibres outside the plaque, some of which were sheered off and others no longer existent. At any rate, the origin of these black formations is not traceable in any case. It seems to be certain that some are related to nerve fibres and some to glial structures. Rather remarkably, numerous preparations produced from very many different areas of the brain did show a single cell with the peculiar fibrillary degeneration which I have previously described. This form of cell change, which occurred very frequently in the other case descriptions of this peculiar disease and which is not infrequently also to be found in severe cases of senile dementia, was missing here, although the plaques were of a size and frequency never seen before in the other cases. So although one might be tempted to do so one cannot relate plaques to fibrillary changes or vice versa. W at the fibril preparation does show in the nerve cells are the disturbances in the fibrillary array which are evidently related to the abundant accumulation of lipoid substances in them. Only rarely do we find a definite 'Reseau pigmentaire' , but in almost all cells, especially at the base, we find numerous spots which are not part .of the fibrillary structures, so that it is often difficult to decide whether they are surrounded by fibrils or by a stained mesh of cytoplasmatic reticulum. Sometimes we also see the cytoplasmic reticulum very clearly at the base of the cell or spread out throughout the protoplasm. Moreover the fibrils show alterations, which have repeatedly been described in Dementia senilis: condensation and granular decay. The cells themselves still have rather widespread dendritic cytoplasmic extensions. In the upper layers a clear sclerosis of very many cells becomes evident. 

As for the plaques in the cerebellum, the overwhelming majority of them appear together in nests up to 20 in the molecular layer. They are mostly very variable in size. Generally such a nest consists of 2-3 large plaques lying in the centre and surrounded by many small ones, sometimes of minute diameter. Ordinarily such an accumulation is closely attached to the surface. Sometimes they are also arranged in a long row vertically towards the surface throughout the whole molecular layer. Others lie in the Purkinje-cell layer or in the granular layer either in isolation or in a group. In the white matter often exceptionally large ones are to be found. Their frequency is considerably less high than in the cerebral cortex. The plaques in the molecular layer often have a core which is much larger than the hole and many in fact have no clearly developed halo at all. In the plaques of the granular layer and in white matter, a halo is evident just as if it is in the cerebral cortex. It should be noted that there is no relevant disturbance of the architecture in the cerebellum. The Purkinje cells are preserved but regularly show a large accumulation of lipoid granules above the core and underneath the main dendrite. In the glial cells, especially those in the Purkinje cell layer, one can see quite regularly-formed lipoid depositions. In Weigert's glial preparation a widespread but not very considerable increase of Bergmann's fibres can be observed. However, where plaques are present in abundance they occur in quite considerable numbers. Interspersed with them one can often see glial cells which have formed complete bundles of fibres with their individual extensions. In general these tend to remain orientated vertically but often avoid the plaques by curving around them like bows. 

In addition Weigert's glial stain preparation shows another unusual finding. One can often see glial fibres, which appear coiled to a remarkable degree (Text fig. 6). A glial fibre extends against one or two adjacent round, pale structures and covers them rather in the way a thread is wound around a coil, finally passing to the other side of the cell. As one can see, the staining properties of the fibre-covered structures are different from the plaque-cores. They do not stain blue but appear reddish in Mann's preparation and with Weigert's glia preparation are hardly stained differently from the background. One has to consider them as Corpora amylacea. In Mann's preparation one can also see glia fibres winding round these structures. This appearance does not seem to me to be without general interest: (1) because they show, what I have already demonstrated earlier, namely that the glia are trying to enclose and support the Corpora amylacea; (2) because they may perhaps shed some light on the physical conditions leading to the development of glial fibres (Homburger). The plaques, which we come across, in the grey masses of the di- and mescephalon, in the grey matter of the pons and in the nuclei of the cranial nerves, are rather similar to those in the cerebral cortex. They mostly have a small core and a large halo. In these areas there is also a striking accumulation of lipoid granules in the nerve cells and widespread increase of fibrous glia. In the spinal cord one does not see much with Weigert's myelin preparations, but with Mann's one gets the impression that in the dorsal columns there is a slight and diffuse increase in glia and in the lateral pyramidal tract a considerable increase of these cells. In the lateral columns one also sees more than a few markedly enlarged and cytoplasm-rich, fibre-forming cells. However, another even better proof for the decay of myelin in the lateral columns is the occurrence of single granular ceIls, single macrophages and of disintegrating small glial elements within the myelin, which are exceptionally weIl seen in Mann's preparation. 

I believe, that the results of the microscopic examination of this case allow us to address a general pathological question, which has been of interest in anatomico-pathological research, as far as it is concerned with the psychoses since FISCHER'S papers. It cannot be doubted that the plaques in these specific cases do in all relevant aspects correspond to those which we find in Dementia senilis. This is evident from the description which other investigators have given about the plaques in Dementia senilis, and this is obvious from the comparisons which PERUSINI, SIMCHOWICZ and I myself have undertaken in quite large amounts of material. Hitherto opinions about the nature of the plaques have been very divergent. To mention only a few, REDLICH, who first described senile plaques, considered them as a glial proliferations. FISCHER, who first denoted them as miliary, plaque-like necroses, later pointed out their similarity to bacterial colonies and reported that he had undertaken cultivation experiments and complement fixation tests, which however produced negative results. H†BNER considered them as deposited detritus. SARTIESCHI declared them to be altered spider cells; PERUSINI, as lumpy, granular and thread-like deposits in an altered glial reticulum; W ADA considered them as circumscribed necroses of nervous parenchyma and of glia. Recently FISCHER declared that he could not come to any definite conclusions, but he considered them 10 be something very special and called the whole disease process 'Sphaerotrichia multiplex cerebri' and remarked 'For me the fibres which show up characteristically with the Bielschowsky's-method are primary and the other corpuscular elements are epiphenomena or after effects.' If the plaques are considered as a whole, preparations using Mann's method in particular show very distinctively that they consist of two parts, one central (core) and one peripheral (halo). This also shows up using Weigert's glial, Herxheimer's lipid and alcohol-toluidine stains, as well as the silver-staining method of Bielschowsky. The core emerges differently with different methods. In spite of this, many of the methods show that it seldom consists of fibrils. I have treated both thick and thin formal-freeze-section after 1, 2, 3, and 4 days with or without pyridine pretreatment in many of the cases discussed here, and have also treated them using Bielschowsky's method. Like HÜBNER I have only relatively rarely seen FISCHER fibrils.The result of repeated experiments was that they sometimes emerged clearly and sometimes were totally absent. Not uncommonly they showed up best in relatively unelaborate preparations but were missing in preparations which might be considered as perfect with respect to the appearance of axis-cylinders and ganglion-cell-fibrils. In most cases, the core presented as a globoid, or nearly globoid, irregular, and fairly uniform structure and often a linie frayed at the margin. More rarely, radial stripes appeared at the margin, and very rarely there occurred areal disintegration into hair-like structures. The same impression was to be gained with all the other numerous methods which I have tried, not all of which have been mentioned here. Specifically, the smallest cores appeared most homogeneous in structure. In the case of F. described here, a specific feature, which I have not come across in other patients, is that the core of the plaque was covered with lipoid granules which could be stained with scarlet and which turned black with Bielschowsky's method. The instability of these structures in comparison to the other deposits which might be coloured scarlet appears to indicate that, if we are dealing with lipid substances, they are of a more unstable kind, and that they differ from other lipoid substances in various cells. I cannot state that they are essential for the formation of plaques as they were not present in all cases. It is also remarkable that in the ca se of F. Weigert's glial-stain a central patch, which turned brown into iodine, always showed up within the core. As FISCHER has underlined, one very rarely sees remnants of nervous tissue within the core. If such tissue is seen, this is usually because the cut has occured near the margin of the core. It appears appropriate to conclude that we have to consider the core of the plaque as an unorganized mass which emerges differently with different staining methods and which with Bielschowsky's method sometimes shows a structure which reminds one of fine needles of crystals. As PERUS IN I and FISCHER have already explained, we are not at present able to identify this mass with any of the substances known in pathological anatomy. The halo of the plaque is much more complex in composition. In Mann's preparation one sees various amorphous masses, lumps and crumbs which are anached to one another and of which parts are a linie brighter, parts a little darker and others hardly taking up any colour at all. Moreover, there occur peculiar club-like excrescences and swellings on the axis cylinders which were first described by FISCHER. As he emphasized, they were not seen in some of the cases but were clearly recognizable in others, as were the connections which they made. FISCHER denies that he was able to establish any relationship between neuroglia and plaques. Quite often glial cells are seen in the plaque-halo in greater or lesser numbers. These are partly transformed into lipid-granular cells, whose content stains greenish with Mann's stain and scarlet with Herxheimer's stain. In the ca se of F. the halo of the plaque is seen to be criss-crossed by extraordinary numbers of glial fibrils whose blue patches give a highly striking appearance to the cortex. This was found not only in F.'s particular case, but I have seen very similar appearances in cases of senile dementia. In other cases one sees such glial-fibre formations only in the plaques which occur in the uppermost cortical layer. In other cases of senile dementia no such glial fibrils can be demonstrated in the plaques. However, after the application of Mallory's stain some plaques are clearly seen to be in contact with cytoplasmatic protrusions of the glial cells which spread normally and show some distortions and cuticular extensions entering the halo of the plaque. Alcohol preparations suffice to demonstrate that the cytoplasm of the glial cells adjacent to the plaque halo changes when entering the halo, presenting striking, fan-like extensions, like a myrtle-twig developing small individualleaves. Finally, even in the Bielschowsky preparations one may notice that although the glial cells are only poorly represented, images occur in relation to the glial cell protrusions, which if not separated from the cell, would hardly be distinguishable from the axis-cylinders. It is therefore beyond doubt that various glial formations occur even in the plaque halo. These take the form of glial granular cells, Weigert's glial fibrils, cy10plasmic glial fibrils or unusual transformations of cytoplasm as compared with those in other glial cells. The description of the plaque would not be complete if we did not conclude that enlarged glial cells quite regularly occur in their immediate surroundings and, when forming fibrils, send these mainly towards plaque and into its halo, and that, as FISCHER has shown, the nervous elements surrounding it appear dislocated. Although some have referred 10 the plaques as debris products, FISCHER is probably right in opposing such a view. One can see the smallest occuring in locations where nothing indicates distintegration of nervous tissue. Thus it is established that they do not arise from degenerated ganglion cells or glial cells, contrary to what has been asserted. For the same reasons, one cannot also speak about necrosis. I believe the plaque core and the halo have to be considered separately. Nothing contradicts, but much supports, the notion that the plaque core owes its origin to the deposition of some still unknown metabolic product in the cerebral cortex. The amorphous substance is changed in different ways by the chemical reagents used in our staining procedures. Its appearance in our preparations is so variable because of this, and it seems inappropriate 10 attribute undue importance to the appearance, as seen in Bielschowsky preparations. That the plaque core is the product of adeposition is further supported by the fact that usually no inclusions which derive from cells can be found within it and that it displaces the surrounding tissue. Today we already know of several metabolic products which are deposited in the cerebral cortex. I want to mention only two: Corpora amylacea and glycogen.   

The most varied opinions have been expressed about the development of the Corpora amylacea. However, everything appears to support the suggestion that they are products which are deposited from the lymphoid fluid perfusing the nervous tissue. Furthermore, we find them appearing in special abundance in the glial spaces immediately underneath the glial membranes and in tissue areas which are completely sclerotic or severely impaired with respect to their nutrition (e.g. in the areas of arteriosclerotic devastation). In the brain they are only found in nervous tissue, not in the adventitiallymphoid spaces or in the pia. That they also occur in other body organs only goes to show that the presence of nervous tissue is not a precondition for their development. These Corpora amylacea mayaiso make the other part of the plaque, i.e. the plaque halo, more understandable. When nervous tissue is investigated by finer methods, one can observe that the Corpora amylacea induce areaction in the surrounding connective tissue. The glia covers it and supports it. I have already described this phenomenon on another occasion. The case of FISCHER offers us a nice opportunity in this regard. In senile dementia Corpora amylacea wrapped with fibrillary glia are at times to be seen lying in the first layer of the cerebral cortex, but these images are not clear, as many other unaltered fibrillary glia can be found as weil. However, in the molecular layer of the cerebellum in F., we see Bergmann's fibres lying quite separately in basket-like formations which cover the Corpora amylacea. While the core of the plaque is evidently formed by the deposition of a pathological metabolic product, we see a number of changes in the halo which have to be interpreted as reactive phenomena, such as occur in different parts of the nervous tissue. Outside the plaque we see large glial cells which send their fibres into the plaque halo rather like an area of miliary softening in cerebral cortex, which is encapsulated by fibre-producing glial cells. We also see other fan-like cytoplasmic glial structures forming and gliogenic granular cells engulfing disintegrating products which are presumably partially derived from nervous elements which decay in the plaque halo and, which perhaps partially from pathological substances, are gradually deposited. Very remarkable and really without precedent in the pathological anatomy of the nervous system are the alterations of axis-cylinders, so exhaustively described by FISCHER. Even if not all the findings described above and not all black staining formations in the plaque halo can be considered as nervous, it cannot be disputed that such tissue is in larger or smaller degree included and that the axis-cylinders form clubbed, fan-like excrescences in the plaque halo. The significance of these formations is still quite unclear. We still know too little about the alterations of the axis-cylinders to express a definitive view about them. In any case, one can sometimes see formations at the axis-cylinders which are perhaps comparable to them. Certainly to some extent they appear to decay rapidly, because often one can see them in a state of disintegration. Even if the plaque cannot be considered as a completely miraculous structure, it must in any ca se represent an extraordinarily characteristic phenomenon.   We now come to the further question of whether these plaques, or as FISCHER calls them 'Sphärotrichia', can be considered as the cause of a quite specific, classifiable and clinically diagnosable psychosis. There are cases of indubitable Dementia senilis, in which the plaques are not very numerous. Moreover, as FISCHER himself stresses, they dislocate the nervous structures more than they destroy them. So the loss of cortical tissue due to the plaques cannot be very considerable. Furthermore, in addition, in places where plaques are not found in the cerebral cortex, we see the well-known widespread senile sclerotic changes, the lipid-pigmented and granular degenerations of ganglion cells with alterations of their fibrils which BRODMANN and BIELSCHOWSKY have described in detail, the fibre-formation of the glia, pigment-accumulation in the glia and the degenerative phenomena in the vessel walls which it is impossible to believe were caused by plaques. These changes are found in the basal ganglia, the medulla, the cerebellum and the spinal cord, although there are no plaques at all in those sites or only isolated ones. So we have to come to the conclusions, that the plaques are not the cause of senile dementia but only an accompanying feature of senile involution of the central nervous system. However, as they seem to occur regularly in larger numbers in presbyophrenic dementia, while only occasional single ones are to be found in advanced age without dementia, they must have as decisive an importance as the diffuse infiltration of the lymphoid vessels with plasma cells. This latter cannot be considered as the cause of paralytic disease but of the paralytic disease process, and is an important diagnostic aid for its recognition. It will certainly remain to Pischer's credit that he was the first to emphasize the importance of the plaques to the histological appearance of senile dementia. As I have pointed out in the connection with other histological findings, Dementia senilis and arteriosclerosis of the brain are in principle different disease processes. This has been proved even more conclusively because of the presence of senile plaques (FISCHER, SIMCHOWICZ). If we now return to our case, we must of course still have reservations in asserting its attribution to the senile disease process solely on the basis of the presence of particularly numerous plaques. This is because, according to our previous thoughts, we can only consider the plaques as an accompanying feature of the senile cortical alterations, and one must first establish how the other alterations which we find in this case relate to those of senile dementia. The fibrillary degeneration of the ganglion cells is absent in this case, while in the cases of such presenile diseases described up to now it was particularly common. We now know that the same cellular degeneration had been observed frequently in cases of severe senile dementia but sometimes it is absent altogether. On the other hand, up to now it has not been found in any disease of younger people. The particularly frequent occurrence in most of the presenile cases might support their relationship to senile dementia. Moreover, we see in this case an extraordinarly heavy accumulation of lipoid substances in the ganglion cells, glial cells and the walls of the vessels, and especially in the numerous fibre-forming  glial cells of the cerebral cortex and indeed in the whole central nervous system. Therefore we observe that all elements are altered in the same manner and direction as in senile dementia, but in this case, as in the others described by PERUSINI, the alterations exceed in their severity the average to be found in Dementia senilis. Finally, in our ca se a decay of sheaths in the white matter in the lateral pyramidal tracts of the spinal cord can be established by the presence of small disintegrating glial cells lying inside the myelin sheath, of myelophages and of granular cells. Whether we are also confronted here with a finding which exceeds what occurs in Dementia senilis, I cannot decide because the spinal cord of Dementia senilis has not yet been investigated in detail by the same methods which might permit the recognition of more subtle losses than by the methods hitherto in use. A further peculiarity of the present case was the localization of the alterations. Even if we were dealing with a diffuse disease of the cortex alone, the parietal and temporal lobes bilaterally were unmistakably especially affected and much more so than the frontal brain. In ordinary cases of senile dementia, the frontal brain is the most severely diseased, as has been found only recently by SIMCHOWICZ. There has been insufficient investigation of the question as to whether, in the other presenile cases described previously, a localization differing in terms of the severity of the changes from these in ordinary senile dementia was also present. If a conclusion based on clinical impression is permitted, individual gyral areas must have been differentially affected with respect to the severity of the changes. However, the differences of the localization of the disease process cannot be used as an argument against relating these forms of dementia to Dementia senilis. After all, we know that the disease process of progressive paralysis allows for the emergence of numerous cases with an atypical localization as well as the majority of cases with a typical one. Further essential facts, which support the membership of such cases to the category of senile dementia, came out of the observations in two cases, which I have investigated recently. Due to circumstances pertaining to the Munich Department it is quite exceptional for patients with advanced Dementia senilis to be examined histologically, since most of these patients are transferred to asylums in earlier stages of the disease. However, amongst the older material made available to me due to the kindness of my former Chief, Herrn Professor SIOLI, I was able to find a case in which alterations had only developed in late old age. Here the number of plaques, the severity of the nerve cell alteration, and the bulk of glial growth were no less severe than in presenile cases. Furthermore, another patient, who became affected only at the end of his sixties with the features of Dementia senilis, which took the form of growing mental impairment with agnostic and aphasic disturbances, developed an extraordinary numerous mass of plaques, extremely wide-spread fibrillary  alterations of the nerve cells and very marked fibrinoid glial growth with uncoordinated sprouting. Hence there appear to be a variety of intermediate forms between these presenile diseases and the typical cases of senile dementia. As similar cases of disease obviously occur in the late old age, it is therefore not exclusively a presenile disease, and there are cases of senile dementia which do not differ from these presenile cases with respect to the severity of disease process. There is then no tenable reason to consider these cases as caused by a specific disease process. They are senile psychoses, atypical forms of senile dementia. Nevertheless, they do assume a certain separate position, so that one has to know of their existence as one has to know about Lissauer's paralysis, in order to avoid misdiagnosis. It will therefore have to be the task of future research to collect a larger number of such cases, which, as the observations in this department show, should not be too rare in order to establish the symptomatology of this group even more clearly, and to substantiate their position with respect to senile dementia on an even firmer basis by proving the existence of further transitional cases. However, why these cases which occur in presenile age are in general accompanied by such exceptionally severe histological alterations and why they cause such exceptionally severe symptoms cannot be answered at the moment. Of course, we know just as little about why paralysis on one occasion affects the whole cerebral cortex with diffuse spread, when in another it bites exceptionally deeply into one particular locus. Anatomical research had taught us that progressive paralysis can occur until the seventies and senile disease processes as early as the forties. So it may be that, just as atypical localizations of the paralytic disease process can cause clinical features which differ greatly from the ordinary features of paralysis, the senile disease process can cause disorders which earlier nobody would nor could have considered as a senile disease process because of the clinical symptoms. These observations, which we had the opportunity of making in two conditions and which are also true for brain-lues, demonstrate to us in an impressive way how difficult it is to define diseases solely with respect to their clinical features, especially in the case of those mental disorders which are caused by an organic disease process. An identical disease process will be able to cause extraordinarily different clinical features because of differences in its localization, and in the sequence and extent of cortical revolvement, which may be diffuse or localized and moreover possibly localized in many different ways. In addition to the discussion of these early cases of senile dementia, I would like to approach another group of senile diseases, to which PICK has devoted a particularly thorough investigation: THE CASES OF CIRCUMSCRIBED ATROPHY. I myself have compared them to Lissauer's paralysis in my paper on paralysis. Naturally the question now arises as to how in the light of progress in histological knowledge of the senile disease processes these cases relate to the just described atypical cases and to typical Dementia senilis. One would expect that a particular  accumulation of plaques and perhaps also of particularly extensive fibrillary degeneration of ganglion cells would be found in the areas of localized atrophy. In two cases which I have seen in the last years, it was striking that no plaques were to be found but there were remarkable alterations in the nerve cells, which once again also primarily concerned the fibrils but were different from the alterations in Dementia senilis, particularly in its early form.  FISCHER has used the term 'gross fibroid fibrillary growth' to apply to the fibrillary alterations which I had first described in one of the cases of the psychoses discussed above. I do not find this name very satisfactory because one cannot call this a fibrillary growth. I cannot add much to my previous description of this ganglion cell disease. Text figures 7, 8, 9, which have all been drawn from one single slice from the cerebral cortex of the first of the cases I have described, are particularly appropriate in order to inform us about its nature. The beginning of the disease can best be demonstrated in the larger pyramidal cells, which in general show these alterations less often than the small ones in the 2nd and 3rd cortical layers. While the remaining fibrils of the cell body and of the dendrites of the diseased cell can mostly only be demonstrated rather faintly, we see single isolated fibrils emerging as exceptionally thick and dark. The alteration here mostly starts in this part of the cell, where again we usually find an abundant deposition of lipid granules. Already at this early stage when the cell has still kept its form quite well, a tendency for the thickened fibrils to clot in bundles or ligaments is seen. In later stages the whole cell becomes altered. The fibrils emerge as various basket- or sling-like intertwined formations on to the periphery of the cell and the cell protoplasm gradually vanishes. Often, however, one can still clearly see the nerve cell core in the middle of the fibrillary basket or sling and sometimes there is only a little structure within the site of the core. Finally, we do not see any nerve cell core in the fibrillary bundle any more but sometimes instead see a glial core which has obviously strayed in, so that the remaining fibrillary bundle can be in the tissue for a long time. The fact that the altered fibrils stain darker and appear thicker, that they can be stained with various methods which do not stain the normal fibril, and that they finally outlast the cellular disintegration, suggests that they have altered chemically - perhaps become impregnated with some substance. That other alterations apart from the formation of fibrils occur in the cytoplasm of the ganglion cell can also be concluded from the fact that they show a peculiar behaviour with basic aniline-dyes, by taking up a faded polish. They appear to be rather swollen, with the core frequently dislodged to the periphery of the cello Recently SIMCHOWICZ has found different forms of this fibrillary degeneration in the Cornu ammonis of senile dementia, the cells of which had turned into a quite homogeneous argentophilic substance. At any rate this represents a profound degenerative alteration of the whole cell which leads to its decay. The fibrils appear altered and are probably also changed in respect to their chemical composition, they seem thickened, outdated and outlive the decay for a long time, probably because of the alteration of their chemical composition. That they are actively thickening or increasing is certainly not to be assumed. We are therefore not dealing with a proliferation of fibrils.  After the description of these fibrillary alterations, those which occur in the ca ses of circumscribed senile atrophy, which initially seemed remarkable, can more easily be understood. In the Bielschowsky preparations (Text fig. 10) we see small pyramidal cells, which, near the nucleus, contain a dark argentophilic globe which is at least half or up to twice as large as the nucleus, and which sometimes does not exhibit any structure. Sometimes it lies above, sometimes below the nucleus displacing it downwards or upwards. In the remaining parts of the cell fibrils do not appear, both the cytoplasm and the axis-cylinder protrusions remain partly visible. These are the most peculiar features in appearance. In other cells we see these argentophilic globes occupying the large part of the cell. Indeed, one also finds cells which consist entirely of such a globe with a nucleus fitting on it like a cap, while the cytoplasm is no longer visible. Occasionally somewhat concentric stripes become recognizable within the globe. In other cells we see greater or smaller gaps occurring in the argentophilic mass, surrounded by fibrillary striped bundles which finally merge into the background. Finally we come across cells which contain fibrillary coils rat her than these globoid formations. The picture may then be more akin to the fibrillary changes in Dementia senilis and its atypical early form. However, I have never seen such bundle formations which are so common in these disorders. Here again the cells which show this fibrillary change can easily be recognized in alcohol-toluidine blue preparations, which demonstrate the curious forms within them - the cap-like riding nucleus which is dislodged in the cytoplasm and the peculiar faintly gleaming colouring of the region where the argentophilic mass lies. It is notable that in the severely atrophic gyri all the preserved cells are altered in the same manner. 

In addition one finds a characteristic condition of the cortical tissue which FISCHER has referred to as 'spongy cortical wasting': that means that the tissue consists principally of vessels, which appear grossly increased in consequence of the enormous atrophy, and of numerous large fibre-forming glial cells which, together with the vessels, build a trabecular connective-tissue. The altered nerve cells lie in the trabeculae. The mesh appears to have been filled with tissue fluid. The myelin sheaths are greatly and diffusely rarefied. Solitary granular cells are visible in the adventitious lymphoid spaces. The diffuse atrophy, with no cell infiltration and the lack of circumscribed foci, permits the exclusion of an arteriosclerotic origin for such localized atrophies. According to FISCHER, one cannot, however, assign these cases to senile dementia as there are no plaques. On the other hand we find a peculiar fibrillary alteration of the nerve cells which I have seen before in arteriosclerosis and which reminds one of Dementia senilis. The question is: are these cases to be assigned to Dementia senilis or to arteriosclerosis? Perhaps such circumscribed atrophies of larger gyral areas occur due to faulty nourishment of the atrophic area following severe arteriosclerotic alterations of a larger artery supplying the whole area, in the same way as smaller severe areas of arteriosclerotic devastation without suppuration occurs quite frequently in the region of severely diseased smaller vessels within the brain substance. I have not specifically examined the large vessels in the last two cases. However, there were probably no arteriosclerotic alterations to be seen in the macroscopic observation. In one case of circumscribed senile brain atrophy one region was 10 be found specifically atrophic and this corresponded to the area of the third branch of the Art. Foss. Sylvii (s.a. V.MONAKOW, Gehirnpathologie II. edition, p. 1087). In my view the fact that the first temporal gyrus was least affected in the first two cases, that the second and third gyri were much more atrophic, and the Cornu ammonis was definitely not less damaged than the second and third temporal gyri, argues against the assumption that the localized atrophy of the 1st temporal lobe is caused by functional factors as PICK has suggested. The Cornu ammonis in any case belongs to quite a different functional area. Perhaps this arrangement of atrophy could be related 10 the vascular supply of the temporal lobe. I am, therefore, not able to make any final conclusions about the circumscribed form of senile brain atrophy but I wanted to communicate my observations because they show the difficulties which still lie in the way of an interpretation of these results. Perhaps they will motivate someone else with new material to answer the questions still awaiting a solution.

(Translation by Hans Förstl and Raymond Levy. A complete version was published in “History of Psychiatry”, 1991)


ALZHEIMER, Histologische Studien zur Differentialdiagnose der progressiven Paralyse. Nissls Arbeiten 1, 18. 1904.

ALZHEIMER, Beiträge zur Kenntnis der pathologischen Neuroglia usw. Nissl-Alzheimers Arbeiten 3, 1. 1910.

BONFIGLIO, Di speciali reperti in un caso di probabile sifilide cerebrale. Rivista sperim. di freniatria 34, 196. 1908.

FISCHER, Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen usw. Monatsschr. f. Psych. u. Neuro!. 22, 361. 1907.

FISCHER, Die presbyophrene Demenz, deren anatomische Grundlage und klinische Abgrenzung. Zeitschr. f. d. ges. Neur. u. Psych. 3, 371,1910.

HÜBNER, Zur Histopathologie der senilen Hirnrinde. Archiv f. Psych. 46, 598. 1909.

KRAEPELIN, Lehrbuch der Psychiatrie. 8. Aufl. 2. 1910.

MYAKE, Beiträge zur Kenntnis der Altersveränderungen der menschlichen Hirnrinde. Obersteiners Arbeiten 13, 212. 1906.

PERUSINI, Über klinisch und histologisch eigenartige psychische Erkrankungen des höheren Lebensalters. Nissl-Alzheimers Arbeiten 3, 297. 1909.

PICK, Zur Symptomatologie der linkseitigen Schläfenlappenatrophie. Monatsschr. f. Psych. u. Neurol. 16. 1904.

PICK, Die umschriebene senile Hirnatrophie als Gegenstand klinischer und anatomischer Forschung. Arbeiten a. d. deutsch. psych. Klinik in Prag. Berlin 1908.

REDLICH, Miliare Sklerose der Hirnrinde. Jahrbücher f. Psych. u. Neurol. 17,208. 1898.

SARTESCHI, Contributo all'istologia patologica della presbiofrenia. Rivesta sperim. di freniatria, 35, 464. 1909.

SIMCHOWICZ, Histologische Studien Über dies senile Demenz. Nissl-Alzheimers Arbeiten, 3, 268. 1911.   


 Impregnation of frozen glia. Weigert's glial fibre stain. Homogenous immersion, Zeiss 1/13. Fig. I drawn after tubus 140, Fig. 2 after tubus 160, ocular 4. 'gaz'. nerve cell, 'glz.' glial cell. 'P' central part (core) of plaque, 'PZ' peripher al part, halo of plaque. Fig. 1: Relationship of fibre-forming glial cell to plaque. Right upper parietal lobulus. In the core of the plaque a small, obviously iodine-stained, dark-brown centre, surrounded by a darker and then brighter ring. The peripheral part is traversed by extraordinarily numerous, immensely subtle glial fibrils, which originate from large glial fibres laying in the margin of the halo. Fig. 2: Massive fibre-forming glial cells enclosing neighbouring nerve cells in the deeper layer of the cortex of the right upper parietal lobe.


Formol freeze cut. Herxheimer's lipid stain. Abbreviations see Table I 'endz.' endothelial cell, 'advz.' advential cell.
Fig. I: The central core of plaque is densely superseded by subtle red-coloured granules. The glial cells in the core of the plaque are glutted with lipoid granules.
Fig.2: Massive accumulation oflipoid material in a plaque near a capillary. 


Fig. 1 Overview of plaques. Slice from the upper half of the cerebral cortex. Mann's stain.  Fig. 2 A rod-shaped glial cell attached to the core of a plaque.  Fig. 3 Two glial cells attached to the core of the plaque. Above a fibre-forming cell, below a grid-cell (granular cell).  Fig.4 Plaque from the deeper cerebral cortex. Bielschoskv stain.  Fig.5. Plaque from the second cortical layer. Bielschowsky stain.
Fig. 6. Corpora amylacea from the molecular layer of the cerebellum woven into Weigert's glial fibres (Weigert's glial stain).  Fig. 7. Peculiar fibrillary changes of the nerve cells. Eariy stage of disease. Bielschowsky stain.
Fig. 8. Peculiar fibrillary changes of the nerve cells. Progressed stage of disease. Bielschowsky stain.
Fig. 9 Peculiar fibrillary changes of the nerve celles. Terminal stages of disease. Bielschowsky stain.
Fig. 10. Peculiar fibrillary changes of the nerve cells in a case of circumscribed senile atrophy. Bielschowsky stain.