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Alzheimer plaques and cortical cholinergic innervation
Neuroscience Vol. 17, No. I, pp. 277-279, Printed in Great Britain
0306-4522/86
1986
$3.00 + 0.00
Pergamon Press Ltd IBRO
REPLY
ALZHEIMER
PLAQUES AND CORTICAL INNERVATION
CHOLINERGIC
T. ARENDT and V. BIGL Paul Plechsig Institute of Brain Research, Dept Neurochemistry, Karl Marx University, 7039 Leipzig, Karl-Marx-Stkdter-Str. 50, German Democratic Republic
In his comments on our paper,* Dr Mesulam raises some very interesting points, which, however, only partially relate directly to the rather specialized topic investigated by us, but refer to more general views and problems of present research strategies in Alzheimer’s disease. As this goes far beyond the aim of our paper some comments from us may be appropriate. It might not be by chance that the brain region which has attracted so much attention during the last few years was originally described as the “unnamed medullary substance”,20 which was the beginning of a still continuing confusion in delineation and nomenclature of this basal forebrain region. For more than one and a half centuries the same brain region was designated by different names and the same names were used by different authors for different parts of the basal forebrain structures. What Koelliker9 ascribed as “basal ganglia” to the name of Meynert clearly refers to the group of neurons extending ventrally to the putamen and globus pallidus from the level of the corpora mammilaria into the septum. It was later that the other nuclei of the basal forebrain (e.g. the nucleus septi medialis, nucleus of the diagonal band, nucleus preopticus magnocellularis) were delineated (see Ref. 4). As summarized in his most extensive and thorough investigation of the cytological organization and phylogenetic development of the basal forebrain, which unfortunately is almost neglected today, Brockhaus4 concluded that although the nuclei of the substantia innominata by cytological criteria and their phylogenetic development must be regarded as different entities, the whole complex forms a topographic unit with neurons of the nucleus basalis distributed throughout the whole area. This concept of a nucleus basalis complex is supported by recent results suggesting similar functional and connectional properties as well as transmitter specificity for these basal forebrain structures. This led USESand other authors’,*’ to adopt the concept of Brockhaus. Taking into account these earlier anatomical descriptions it is far from clear what is the “traditional” designation of the nucleus basalis.
It is the merit of the alternative nomenclature for these cholinergic basal forebrain structures put forward by Dr Mesulam and his colleagues to overcome this confusion in nomenclature and to provide a reliable frame to address and describe the different groups and subgroups of choline@ neurons overlapping with the traditional neuroanatomic borderlines. We acknowledge that it was also Dr Mesulam and his group who first identified identical Ch-sectors in monkey and humans; we only adapted his nomenclature in a simplified manner for our investigation. Since there is no detailed information about the cortical projection pattern of the basal nucleus complex in human brain, our studies were based on retrograde labelling experiments in monkey’* and rat3 as well as the pattern of retrograde degeneration after cortical damage in humans.’ In the case described by Kodama,* the main lesion which led to extensive neuronal loss in the posterior parts of the nucleus basalis involved the frontal half of the inferior temporal gyrus, superior temporal gyrus and occipitotemporal gyrus as well as the frontal third of the middle temporal gyrus, which essentially correspond to Brodmann areas 20, 21, 22 and 38. Actually, plaque counts of each of these cortical areas correlate with neuronal loss in the Ch 4p sector. In our paper we concentrated on area 20, which in monkey, besides its principal projections to the superior temporal gyrus and the temporal pole, has a substantial projection to the infratemporal region.‘* This approach was substantiated later by the finding of Dr Mesulam13 who demonstrated a reciprocal innervation between temporopolar and superior temporal areas resp. and the Ch 4p sector, which might additionally modify the relationship between degeneration of the nucleus basalis and cortical plaque formation. Whether the projection pattern in humans is slightly different to that in monkeys or whether other factors may influence the relationship between neuronal loss in the nucleus basalis and plaque counts in its cortical target areas, remain to be established in further studies. Until now it has been difficult to speculate in what way the different intensity of the cortical cholinergic 277
27X
T. .AHFNDT
innervation might be related to a different regional vulnerability in individual cases of Alzhcimer’s disease. Areas with the least amount of intrinsic cholinergic innervation might not necessarily be expected to have the least plaque density, since it seems likely, as already discussed by Mesulam,“’ that cortical areas with a less dense cholinergic innervation are especially vulnerable to a decrement of acetylcholine. The issue on the primary pathological lesion in the brain in Alzheimer’s disease raised by Dr Mesulam is indeed not settled and we agree that actually our results are compatible with both primary degenerative changes at the level of the nucleus basalis, or retrograde degeneration of subcortical structures due to primary cortical damage. In our view. however, several lines of evidence make it rather unlikely that the degeneration of subcortical neurons in the nucleus basalis or locus coeruleus is simply a secondary event to a primary cortical pathology in Alzheimer’s disease. (i) Evidence for a retrograde degeneration of neurons in the nucleus basalis after cortical lesion is still controversial. Circumscribed cortical lesions in rat,” rabbits and monkey I7 have failed to produce noticeable neuronal loss in the nucleus basalis, but only a shrinkage of these cholinergic neurons could be Even after hemispherectomy and observed. leucotomy” or extensive cortical lesion,*,‘9 these neurons persisted for several years in a shrunken form and neuronal loss remained uncertain. On the other hand, neuronal loss in the nucleus basalis was reported in rat,” young rabbit,5 young dog and kitten,’ monkey’” and in a child with extensive cortical lesions involving temporal cortex,8 but no quantitative data were provided. The reasons for these discrepancies are still not clear, but size and location of the cortical lesion as well as age of the animals and survival time after the lesion Seem to be crucial for inducing neuronal loss in the nucleus basalis. In this respect it might be of interest that in Golgi-impregnated sections at the level of the nucleus of the diagonal band and the substantia innominata in dogs, a number of neurons with axon bifurcations near to the cell body have been observed,” which seems to indicate the existence of several target areas for one single neuron. These neurons, which belong to the reticular class of neurons, are similar in the size and shape of their perikarya as well as dendritic pattern to the cholinergic neurons. In addition, branched projections from neurons of the nucleus basalis to neocortex and neostriatum have recently been demonstrated in cat.6 This would explain why, after circumscribed lesions affecting only one part of the neuronal periphery, the neurons do not degenerate completely, but persist in a shrunken form. The same seems to be true for neurons of the locus colwith their extensive axonal coeruleus lateralization. where even after extensive cortical damage in monkey and humans no noticeable neuronal loss could be observed.” All the cases of
and V. BK;I Alzheimer’s disease WC have morphometrically investigated so far revealed a dramatic neuronal loss in the nucleus basalis complex. which was not necessarily accompanied by a similar neuronal loss in the locus coeruleus. Only one group of patients. especially severe pre-senile cases, was characterized by both severe reduction of neurons in the nucleus basalis and in the locus coeruleus by about SO-80%. In other groups, especially senile cases, neuronal loss of comparable size in the nucleus basalis was accompanied by only a slight decrease in neuronal counts in the locus coeruleus by IO-30% (unpublished results). It seems worth mentioning that plaque density does not simply reflect the severity of cortical degeneration as implied in Dr Mesulam’s comment, as no correlation of plaque density and cortical thickness or cortical neuronal loss could be observed in Alzheimer’s diseaseSz3 (ii) It is well recognized that the reduction of cholinergic neurons in the nucleus basalis and the concomitant decrease of cholinergic projections to the cerebral cortex is not specific for Alzheimer’s disease but can be observed in a number of other neuropsychiattic disorders associated with dementia with widely different pathogenetic mechanisms (and possibly different cortical pathology) involved. As already discussed elsewhere,’ the involvement of the choline@ basalis neurons common to all these disorders may indicate that this structure is especially susceptible to a variety of different agents and conditions including retrograde changes. Whether other cholinergic neurons for which no cortical projections are known so far are really spared in Alzheimer’s disease., as mentioned by Dr Mesulam, Whereas of controversy. is still a matter acetylcholinesterase-containing neurons in the neostriatum were found to be unaltered,” a reduction of the activity of cholineacetyltransferase in the caudate nucleusI and the lumbar spinal cord*’ by almost two third remains to be explained. From the data available so far, it seems to us that the processes of degeneration in the cerebral cortex, as reflected by the formation of neuritic plaques and the neuronal loss in the nucleus basalis, are connected in a much more complex way than is provided for by either of the hypotheses presently under consideration. As discussed previously,’ cortical plaque formation and neuronal loss in the nucleus basalis complex reveals an exponential relationship which might involve what we called a process of self perpetuation. The demonstration of a reciprocal innervation of the different Ch groups and some cortical areas” might be the morphological substrate for such a mechanism. Thus the question of a primary pathological lesion in the brain in Alzheimer’s disease may actually only reflect our very limited understanding of the brain and its function. Its heuristic value lies in the fact that it might hopefully lead to the modelling of circum-
279
Reply scribed steps of the pathomechanism disease.
of Alzheimer’s
REFERENCES 1. Arendt T., Big1 V. and Arendt A. (1984) Neurone loss
2.
3.
4. 5.
in the nucleus basalis of Meynert in Creutzfeldt-Jakob disease. Acta neuroparhol. 65, 85-88. Arendt T., Big1 V., Tennstedt A. and Arendt A. (1985) Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer’s disease. Neuroscience 14, l-14. Big1V., Woolf N. J. and Butcher L. L. (1982) Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital and cingulate cortices: a combined fluorescent tracers and acetylcholinesterase analysis. Brain Res. Bull. 8, 727-750. Brockhaus H. (1942) Vergleichend-anatomische Untersuchungen iiber den Basalkernkomplex. J. Psychol. Neurol. 52, 51-95. Das G. D. (1971) Proiections of the interstitial nerve cells surrounding the globus pallidus: a study of retrograde changes following cortical ablations in rabbits. Z. Anat. Enrwickl.-Gesch.
133. 135-160.
6. Fisher R. S., Boylan M. K., Hull Ch. D., Buchwald N. A. and Levine M. S. (1985) Branched nroiections of pallidal and peripallidal neurons to neocortex and neostriatum: a double-labeling study in the cat. Brain Res. 326, 156-159.
I. Jones E. G., Burton H., Saper C. B. and Swanson L. W. (1976) Midbrain, diencephalic and cortical relationship of the basal nucleus of Meynert and associated struttures in primates. J. camp. Neurol. 167, 385-420. 8. Kodama S. (1927) Ober die sogenannten Basalganglien. II. Pathologisch-anatomische Untersuchungen mit Bezug auf did sogenannten Basalganglien und ihre Adnexe. Schweizer Archiv Neural. Psvchiat. 20, 209-261. 9. Koelliker A. (1896) Handbuch der Gewebelehre des Menschen. Band 2, Nervensystem Thiere. Engelmann, Leipzig.
des Menschen und der
10. Lehmann J., Nagy I., Atmadja S. and Fibiger H. C. (1980) The nucleus basalis magnocellularis: the origin of a cholinergic projection to the neocortex of the rat. Neuroscience 5, 1161-1174. 11. Leontovich T. A. Personal communication. 12. Mesulam M.-M., Mufson E. J., Levey A. I. and Wainer B. H. (1983) Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. .I. camp. Neurol. 214, 170-197.
MC.
1711-N
13. Mesulam M.-M. and Mufson E. J. (1984) Neuronal inputs into the nucleus basalis of the substantia innominata (Ch 4) in the rhesus monkey. Bruin 107, 253-274. 14. Mesulam M.-M., Rosen A. D. and Mufson E. J. (1984) Regional variations in cortical choline@ innervation: chemoarchitectonics of acetylcholinesterase-containing fibers in the macaque brain. Brain Res. 311, 245-258. 15. Parent A., Csonka C. and Etienne P. (1984) The occurrence of large acetylcholinesterase-containing neurons in human neostriatum as disclosed in normal and Alzheimer-diseased brains. Brain Res. 291, 154- 158. 16. Pearce B. R.. Palmer A. M.. Bowen S. M.. Wilcock G. K., Esiri M. M. and Davison A. N. (1984) Neurotransmitter dysfunction and atrophy of the caudate nucleus in Alzheimer’s disease. Neurochem. Pathol. 2, 221-232. 17. Pearson R. C. A., Gatter K. C. and Powell T. P. S.
(1983) Retrograde cell degeneration in the basal nucleus in monkey and man. Bruin Res. 261, 321-326. 18. Pilleri G. (1962) Ober die Verbindungen des Nucleus basalis Meynert mit der Temporalhirnrinde. Acra anat. SO, 389. 19. Pilleri G. (1966) Weitere Beobachtung zur Frage der Projektion des Ganglion basale Meynert (Nucleus ansae lenticularis) beim Menschen. Acta unut. 65, 138-145. 20. Reil J. C.‘(l809) Untersuchungen fiber den Bau des grogen Gehirns im Menschen. Arch. Physiol. 9, 137-146. 21. Saper C. B. (1984) Organization
of cerebral cortical afferent systems in the rat. II. Magnocellular basal nucleus. J. camp. Neurol. 222, 313-342. 22. Sofroniew M. W., Pearson R. C. A., Eckenstein F., Cue110 A. C. and Powell T. P. S. (1983) Retrograde changes in cholinergic neurons in the basal forebrain of the rat following cortical damage. Brain Res. 289, 370-374. 23. Terry R. D., Peck A., DeTeresa R., Schechter R. and
Horoupian D. S. (1981) Some morphometric aspects of the brain in senile dementia of the Alzheimer’s type. Ann. Neural. 10, 184-192. 24. Wenk H., Big1 V. and Meyer U. (1980) Cholinergic projections from magnocellular nuclei of the basal forebrain to cortical areas in rats. Bruin Res. Rev. 2, 295-316.
25. Yates C. M., Harmar A. J., Rosie R., Sheward J., Sanchez de Levy G., Simpson J., Maloney A. F. J., Gordon A. and Fink G. (1983) Thyrotropin-releasing hormone, luteinizing hormone-releasing hormone and substance P immuno-reactivity in post-mortem brain from cases Alzheimer-type dementia and Down’s syndrome. Brain Res. 258, 45-52.
0306-4522/86
1986
$3.00 + 0.00
Pergamon Press Ltd IBRO
REPLY
ALZHEIMER
PLAQUES AND CORTICAL INNERVATION
CHOLINERGIC
T. ARENDT and V. BIGL Paul Plechsig Institute of Brain Research, Dept Neurochemistry, Karl Marx University, 7039 Leipzig, Karl-Marx-Stkdter-Str. 50, German Democratic Republic
In his comments on our paper,* Dr Mesulam raises some very interesting points, which, however, only partially relate directly to the rather specialized topic investigated by us, but refer to more general views and problems of present research strategies in Alzheimer’s disease. As this goes far beyond the aim of our paper some comments from us may be appropriate. It might not be by chance that the brain region which has attracted so much attention during the last few years was originally described as the “unnamed medullary substance”,20 which was the beginning of a still continuing confusion in delineation and nomenclature of this basal forebrain region. For more than one and a half centuries the same brain region was designated by different names and the same names were used by different authors for different parts of the basal forebrain structures. What Koelliker9 ascribed as “basal ganglia” to the name of Meynert clearly refers to the group of neurons extending ventrally to the putamen and globus pallidus from the level of the corpora mammilaria into the septum. It was later that the other nuclei of the basal forebrain (e.g. the nucleus septi medialis, nucleus of the diagonal band, nucleus preopticus magnocellularis) were delineated (see Ref. 4). As summarized in his most extensive and thorough investigation of the cytological organization and phylogenetic development of the basal forebrain, which unfortunately is almost neglected today, Brockhaus4 concluded that although the nuclei of the substantia innominata by cytological criteria and their phylogenetic development must be regarded as different entities, the whole complex forms a topographic unit with neurons of the nucleus basalis distributed throughout the whole area. This concept of a nucleus basalis complex is supported by recent results suggesting similar functional and connectional properties as well as transmitter specificity for these basal forebrain structures. This led USESand other authors’,*’ to adopt the concept of Brockhaus. Taking into account these earlier anatomical descriptions it is far from clear what is the “traditional” designation of the nucleus basalis.
It is the merit of the alternative nomenclature for these cholinergic basal forebrain structures put forward by Dr Mesulam and his colleagues to overcome this confusion in nomenclature and to provide a reliable frame to address and describe the different groups and subgroups of choline@ neurons overlapping with the traditional neuroanatomic borderlines. We acknowledge that it was also Dr Mesulam and his group who first identified identical Ch-sectors in monkey and humans; we only adapted his nomenclature in a simplified manner for our investigation. Since there is no detailed information about the cortical projection pattern of the basal nucleus complex in human brain, our studies were based on retrograde labelling experiments in monkey’* and rat3 as well as the pattern of retrograde degeneration after cortical damage in humans.’ In the case described by Kodama,* the main lesion which led to extensive neuronal loss in the posterior parts of the nucleus basalis involved the frontal half of the inferior temporal gyrus, superior temporal gyrus and occipitotemporal gyrus as well as the frontal third of the middle temporal gyrus, which essentially correspond to Brodmann areas 20, 21, 22 and 38. Actually, plaque counts of each of these cortical areas correlate with neuronal loss in the Ch 4p sector. In our paper we concentrated on area 20, which in monkey, besides its principal projections to the superior temporal gyrus and the temporal pole, has a substantial projection to the infratemporal region.‘* This approach was substantiated later by the finding of Dr Mesulam13 who demonstrated a reciprocal innervation between temporopolar and superior temporal areas resp. and the Ch 4p sector, which might additionally modify the relationship between degeneration of the nucleus basalis and cortical plaque formation. Whether the projection pattern in humans is slightly different to that in monkeys or whether other factors may influence the relationship between neuronal loss in the nucleus basalis and plaque counts in its cortical target areas, remain to be established in further studies. Until now it has been difficult to speculate in what way the different intensity of the cortical cholinergic 277
27X
T. .AHFNDT
innervation might be related to a different regional vulnerability in individual cases of Alzhcimer’s disease. Areas with the least amount of intrinsic cholinergic innervation might not necessarily be expected to have the least plaque density, since it seems likely, as already discussed by Mesulam,“’ that cortical areas with a less dense cholinergic innervation are especially vulnerable to a decrement of acetylcholine. The issue on the primary pathological lesion in the brain in Alzheimer’s disease raised by Dr Mesulam is indeed not settled and we agree that actually our results are compatible with both primary degenerative changes at the level of the nucleus basalis, or retrograde degeneration of subcortical structures due to primary cortical damage. In our view. however, several lines of evidence make it rather unlikely that the degeneration of subcortical neurons in the nucleus basalis or locus coeruleus is simply a secondary event to a primary cortical pathology in Alzheimer’s disease. (i) Evidence for a retrograde degeneration of neurons in the nucleus basalis after cortical lesion is still controversial. Circumscribed cortical lesions in rat,” rabbits and monkey I7 have failed to produce noticeable neuronal loss in the nucleus basalis, but only a shrinkage of these cholinergic neurons could be Even after hemispherectomy and observed. leucotomy” or extensive cortical lesion,*,‘9 these neurons persisted for several years in a shrunken form and neuronal loss remained uncertain. On the other hand, neuronal loss in the nucleus basalis was reported in rat,” young rabbit,5 young dog and kitten,’ monkey’” and in a child with extensive cortical lesions involving temporal cortex,8 but no quantitative data were provided. The reasons for these discrepancies are still not clear, but size and location of the cortical lesion as well as age of the animals and survival time after the lesion Seem to be crucial for inducing neuronal loss in the nucleus basalis. In this respect it might be of interest that in Golgi-impregnated sections at the level of the nucleus of the diagonal band and the substantia innominata in dogs, a number of neurons with axon bifurcations near to the cell body have been observed,” which seems to indicate the existence of several target areas for one single neuron. These neurons, which belong to the reticular class of neurons, are similar in the size and shape of their perikarya as well as dendritic pattern to the cholinergic neurons. In addition, branched projections from neurons of the nucleus basalis to neocortex and neostriatum have recently been demonstrated in cat.6 This would explain why, after circumscribed lesions affecting only one part of the neuronal periphery, the neurons do not degenerate completely, but persist in a shrunken form. The same seems to be true for neurons of the locus colwith their extensive axonal coeruleus lateralization. where even after extensive cortical damage in monkey and humans no noticeable neuronal loss could be observed.” All the cases of
and V. BK;I Alzheimer’s disease WC have morphometrically investigated so far revealed a dramatic neuronal loss in the nucleus basalis complex. which was not necessarily accompanied by a similar neuronal loss in the locus coeruleus. Only one group of patients. especially severe pre-senile cases, was characterized by both severe reduction of neurons in the nucleus basalis and in the locus coeruleus by about SO-80%. In other groups, especially senile cases, neuronal loss of comparable size in the nucleus basalis was accompanied by only a slight decrease in neuronal counts in the locus coeruleus by IO-30% (unpublished results). It seems worth mentioning that plaque density does not simply reflect the severity of cortical degeneration as implied in Dr Mesulam’s comment, as no correlation of plaque density and cortical thickness or cortical neuronal loss could be observed in Alzheimer’s diseaseSz3 (ii) It is well recognized that the reduction of cholinergic neurons in the nucleus basalis and the concomitant decrease of cholinergic projections to the cerebral cortex is not specific for Alzheimer’s disease but can be observed in a number of other neuropsychiattic disorders associated with dementia with widely different pathogenetic mechanisms (and possibly different cortical pathology) involved. As already discussed elsewhere,’ the involvement of the choline@ basalis neurons common to all these disorders may indicate that this structure is especially susceptible to a variety of different agents and conditions including retrograde changes. Whether other cholinergic neurons for which no cortical projections are known so far are really spared in Alzheimer’s disease., as mentioned by Dr Mesulam, Whereas of controversy. is still a matter acetylcholinesterase-containing neurons in the neostriatum were found to be unaltered,” a reduction of the activity of cholineacetyltransferase in the caudate nucleusI and the lumbar spinal cord*’ by almost two third remains to be explained. From the data available so far, it seems to us that the processes of degeneration in the cerebral cortex, as reflected by the formation of neuritic plaques and the neuronal loss in the nucleus basalis, are connected in a much more complex way than is provided for by either of the hypotheses presently under consideration. As discussed previously,’ cortical plaque formation and neuronal loss in the nucleus basalis complex reveals an exponential relationship which might involve what we called a process of self perpetuation. The demonstration of a reciprocal innervation of the different Ch groups and some cortical areas” might be the morphological substrate for such a mechanism. Thus the question of a primary pathological lesion in the brain in Alzheimer’s disease may actually only reflect our very limited understanding of the brain and its function. Its heuristic value lies in the fact that it might hopefully lead to the modelling of circum-
279
Reply scribed steps of the pathomechanism disease.
of Alzheimer’s
REFERENCES 1. Arendt T., Big1 V. and Arendt A. (1984) Neurone loss
2.
3.
4. 5.
in the nucleus basalis of Meynert in Creutzfeldt-Jakob disease. Acta neuroparhol. 65, 85-88. Arendt T., Big1 V., Tennstedt A. and Arendt A. (1985) Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer’s disease. Neuroscience 14, l-14. Big1V., Woolf N. J. and Butcher L. L. (1982) Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital and cingulate cortices: a combined fluorescent tracers and acetylcholinesterase analysis. Brain Res. Bull. 8, 727-750. Brockhaus H. (1942) Vergleichend-anatomische Untersuchungen iiber den Basalkernkomplex. J. Psychol. Neurol. 52, 51-95. Das G. D. (1971) Proiections of the interstitial nerve cells surrounding the globus pallidus: a study of retrograde changes following cortical ablations in rabbits. Z. Anat. Enrwickl.-Gesch.
133. 135-160.
6. Fisher R. S., Boylan M. K., Hull Ch. D., Buchwald N. A. and Levine M. S. (1985) Branched nroiections of pallidal and peripallidal neurons to neocortex and neostriatum: a double-labeling study in the cat. Brain Res. 326, 156-159.
I. Jones E. G., Burton H., Saper C. B. and Swanson L. W. (1976) Midbrain, diencephalic and cortical relationship of the basal nucleus of Meynert and associated struttures in primates. J. camp. Neurol. 167, 385-420. 8. Kodama S. (1927) Ober die sogenannten Basalganglien. II. Pathologisch-anatomische Untersuchungen mit Bezug auf did sogenannten Basalganglien und ihre Adnexe. Schweizer Archiv Neural. Psvchiat. 20, 209-261. 9. Koelliker A. (1896) Handbuch der Gewebelehre des Menschen. Band 2, Nervensystem Thiere. Engelmann, Leipzig.
des Menschen und der
10. Lehmann J., Nagy I., Atmadja S. and Fibiger H. C. (1980) The nucleus basalis magnocellularis: the origin of a cholinergic projection to the neocortex of the rat. Neuroscience 5, 1161-1174. 11. Leontovich T. A. Personal communication. 12. Mesulam M.-M., Mufson E. J., Levey A. I. and Wainer B. H. (1983) Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. .I. camp. Neurol. 214, 170-197.
MC.
1711-N
13. Mesulam M.-M. and Mufson E. J. (1984) Neuronal inputs into the nucleus basalis of the substantia innominata (Ch 4) in the rhesus monkey. Bruin 107, 253-274. 14. Mesulam M.-M., Rosen A. D. and Mufson E. J. (1984) Regional variations in cortical choline@ innervation: chemoarchitectonics of acetylcholinesterase-containing fibers in the macaque brain. Brain Res. 311, 245-258. 15. Parent A., Csonka C. and Etienne P. (1984) The occurrence of large acetylcholinesterase-containing neurons in human neostriatum as disclosed in normal and Alzheimer-diseased brains. Brain Res. 291, 154- 158. 16. Pearce B. R.. Palmer A. M.. Bowen S. M.. Wilcock G. K., Esiri M. M. and Davison A. N. (1984) Neurotransmitter dysfunction and atrophy of the caudate nucleus in Alzheimer’s disease. Neurochem. Pathol. 2, 221-232. 17. Pearson R. C. A., Gatter K. C. and Powell T. P. S.
(1983) Retrograde cell degeneration in the basal nucleus in monkey and man. Bruin Res. 261, 321-326. 18. Pilleri G. (1962) Ober die Verbindungen des Nucleus basalis Meynert mit der Temporalhirnrinde. Acra anat. SO, 389. 19. Pilleri G. (1966) Weitere Beobachtung zur Frage der Projektion des Ganglion basale Meynert (Nucleus ansae lenticularis) beim Menschen. Acta unut. 65, 138-145. 20. Reil J. C.‘(l809) Untersuchungen fiber den Bau des grogen Gehirns im Menschen. Arch. Physiol. 9, 137-146. 21. Saper C. B. (1984) Organization
of cerebral cortical afferent systems in the rat. II. Magnocellular basal nucleus. J. camp. Neurol. 222, 313-342. 22. Sofroniew M. W., Pearson R. C. A., Eckenstein F., Cue110 A. C. and Powell T. P. S. (1983) Retrograde changes in cholinergic neurons in the basal forebrain of the rat following cortical damage. Brain Res. 289, 370-374. 23. Terry R. D., Peck A., DeTeresa R., Schechter R. and
Horoupian D. S. (1981) Some morphometric aspects of the brain in senile dementia of the Alzheimer’s type. Ann. Neural. 10, 184-192. 24. Wenk H., Big1 V. and Meyer U. (1980) Cholinergic projections from magnocellular nuclei of the basal forebrain to cortical areas in rats. Bruin Res. Rev. 2, 295-316.
25. Yates C. M., Harmar A. J., Rosie R., Sheward J., Sanchez de Levy G., Simpson J., Maloney A. F. J., Gordon A. and Fink G. (1983) Thyrotropin-releasing hormone, luteinizing hormone-releasing hormone and substance P immuno-reactivity in post-mortem brain from cases Alzheimer-type dementia and Down’s syndrome. Brain Res. 258, 45-52.