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Alzheimer plaques and cortical cholinergic innervation
0306-4522/86 53.00 + 0.00
Neuroscience Vol. 17, No. I, pp. 275-276, 1986 Printed in Great Britain
PergamonPressLtd IBRO
MATTER
ALZHEIMER
ARISING
PLAQUES AND CORTICAL INNERVATION
CHOLINERGIC
M-M. ME~ULAM Division of Neuroscience and Behavioral Neurology, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215. U.S.A.
The recently published paper by Arendt and colleagues’ deserves considerable praise. Although the loss of nucleus basalis neurons in Alzheimer’s disease has attracted intense attention for several years, this is perhaps the first study in which the level of anatomical sophistication fits the complexity of this region and the details of its cortical projections. Experimental studies in the monkey have shown that the organization of cholinergic projections from the basal forebrain to cortical subregions displays an intricate topographic arrangement.6 One interesting implication of the study by Arendt et al. is that the corresponding projections in the human brain may follow a very similar pattern. However, the paper also raises several points which, need further clarification and comment. For reasons that have been described in detail previously, we proposed an alternative nomenclature for the four major cholinergic cell groups in the basal forebrain.6 Accordingly, the cholinergic neurons within the medial septal nucleus were designated as Chl, those within the vertical limb nucleus of the diagonal band of Broca as Ch2, those within the horizontal limb nucleus of the diagonal band as Ch3 and those within the nucleus basalis of Meynert and associated cell groups as Ch4. Furthermore, we subdivided the very extensive Ch4 group into anteromedial (CMam), anterolateral (CMal), intermediate (Ch4i) and posterior (Ch4p) subsectors. Arendt et al. imply that the nucleus basalis collectively corresponds to Chl + Ch2 + Ch4. This is not entirely accurate; only Ch4 and its subsectors correspond to the traditional designation of nucleus basalis. Although most of the detail in our paper was focused on the brain of the monkey, we also specifically stated that identical Ch sectors could be identified in the human brain. In fact, we included photomicrographs of the human basal forebrain and indicated the putative location of Chl, Ch2, Ch3am, Ch4a1, and Ch4i.6 Arendt et al. follow this designation very closely and we agree with their labeling of the relevant forebrain cell groups according to the Ch nomenclature. However, there are some potential discrepancies in the way the topography of projections from Ch4 to cortical areas has been interpreted.
For example, we specified that CMam is a major source of cholinergic input only to the medial aspect of area 7, not to its dorsolateral parts. Arendt et al. assume a relationship between Ch4am and area 7 without specifying which part of area 7 was examined. Secondly, they imply a relationship between Ch4p and area 20 in the temporal lobe. However, our results had shown that Ch4p is the major source of cholinergic input only to the superior temporal gyrus (area 22) and the temporal pole (area 38). Area 20 which is more ventrally located in the temporal lobe would correspond to the projection area not of Ch4p but CMi (assuming, of course, that the projection patterns in man are topographically analogous to those in the monkey). With the exception of these two inconsistencies, the interpretation of the projection patterns of the other subsectors is essentially accurate. The authors state that their results support “the hypothesis of a cholinergic pathogenesis of neuritic plaques” (Ref. 3, p. 12). According to this position, plaques are largely due to degenerated cholinergic endings. Plaque density therefore reflects the extent of neuronal loss in the nucleus basalis. However, if the nucleus basalis (Ch4) is the primary site of predilection in Alzheimer’s disease and if the destruction of these neurons gives rise to plaques, then on average, areas with the least amount of intrinsic cholinergic innervation might be expected to have the least plaque density. In the monkey brain, we showed that association areas in prefrontal, posterior parietal and lateral temporal regions have the least amount of cholinergic innervation.’ Nonetheless, on average, these areas contain among the highest plaque counts in patients with Alzheimer’s disease.5 Primary sensory areas, on the other hand, despite a higher cholinergic innervation than association areas, have the least amount of plaques.5 Therefore, the relative intensity of cortical cholinergic innervation (as described in the monkey brain) does not appear to predict the selective regional vulnerability to the formation of plaques in Alzheimer’s disease. One way to reconcile this potential discrepancy is to accept a different hypothesis which is also acknowledged as a legitimate alternative by Arendt 215
276
\I-M.
and colleagues (Ref. 3. p. 12). According to this alternative, the primary pathology is in the cortex rather than in the nucleus basalis.‘,4.” In that case. the plaque density would simply reflect the severity of cortical involvement by the unknown pathogen. Cortical involvcmcnt could then give rise to sccondary retrograde or trans-synaptic degeneration within the cholinergic neurons of the basal forebrain. Since such secondary effects occur only along established neural pathways, the basal forebrain cell loss would bc most severe in the Ch sectors which project to the cortical areas that have the greatest plaque density (hence the most severe pathology). This expectation is consistent with the results of Arendt ct al. The hypothesis of a primary cortical pathology followed by secondary degeneration of subcortical neurons also provides a simple explanation for the rather puzzling fact that cholinergic neurons which do not project to cortex (such as those in the striatum) are spared in Alzheimer’s disease, whereas noncholinergic neurons with cortical projections (such as those in the brainstem rdphe and nucleus locus ceruleus) show degenerative changes. Another observation by Arendt et al. indicates that the neuronal count in the basal forebrain cholinergic cell groups is slightly higher in the right hemisphere than in the left. This deserves comment in view of the observation by Amaducci and colleagues that the temporal neocortex in the left hemisphere contains a higher level of choline acetyltransferase activity.’ Since choline acetyltransferase is a specific presynaptic marker for cholinergic innervation and since the major source of this innervation is in the basal forebrain, this finding might have led to the prediction that there would be more cortically projecting cholinergic neurons in the left hemisphere than in the right, especially since these cholinergic cells have almost no crossed cortical projections. The findings
MCSCL.AS~
by Arendt er al. clearly show that the asymmrtry 01’ cortical choline acetyltransferase. if confirmed by further studies. will need a different and probably more complex explanation. Let me conclude by stating that I found the paper by Arendt ef al.‘ very informative. Thanks to the detailed analysis that it provides, it is now possible to ask more quantitative questions which will hopefully become the focus of further investigations. REFERENCFS
1. Amaducci L., Sorbi S.. Albanese A. and Gainotti G.
2.
3.
4
5
(1981) Choline acetyltransferase (ChAT) activity differ in right and left human temporal lobes. Neurolr>gv 31, 799-805. Appel S. H. (1981) A unifying hypothesis for the cause of amyotrophic lateral sclerosis, parkinsonism and Alzheimer’s disease. Ann. Neurol. 10, 499-505. Arendt T., Bigl 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, I -14. Bloxam C. A., Perry E. K., Perry R. H. and Candy J. M. (1984) Neuropathological and neurochemical correlates of Alrheimer-type and parkinsonian dementia. In Alzheimer’s Disease: Advances in Basic Research and Therapies. (eds Wurtman R. J., Corkin S. H. and Growdon J. H.). pp. 39-52. Center for Brain Sciences and Metabolism Charitable Trust. Cambridge. Massachusetts. Kemper T. (1984) Neuroanatomical and neuropathological changes in normal aging and deme&a. In Clinical Neurolonv Aainn (ed. Albert M. L.). DD. 9-52. ’ ’’ Oxford University Press. New York. Mesulam M-M.. Mufson E. J., Levey A. I. and Wainer B. H. (1983) Choline@ innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus baaalis (substantia innominata) and hypothalamus in the rhesus monkey. J. camp. Neural. 214, 170-197. Mesulam M-M., Rosen A. D. and Mufson E. J. (1984) Regional variations in cortical cholinergic innervation: chemoarchitectonics of acetylcholinesterase-cantaining fibers in the macaque brain. Bruin Res. 311, 245-258. ..I
6
7
__.
Neuroscience Vol. 17, No. I, pp. 275-276, 1986 Printed in Great Britain
PergamonPressLtd IBRO
MATTER
ALZHEIMER
ARISING
PLAQUES AND CORTICAL INNERVATION
CHOLINERGIC
M-M. ME~ULAM Division of Neuroscience and Behavioral Neurology, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215. U.S.A.
The recently published paper by Arendt and colleagues’ deserves considerable praise. Although the loss of nucleus basalis neurons in Alzheimer’s disease has attracted intense attention for several years, this is perhaps the first study in which the level of anatomical sophistication fits the complexity of this region and the details of its cortical projections. Experimental studies in the monkey have shown that the organization of cholinergic projections from the basal forebrain to cortical subregions displays an intricate topographic arrangement.6 One interesting implication of the study by Arendt et al. is that the corresponding projections in the human brain may follow a very similar pattern. However, the paper also raises several points which, need further clarification and comment. For reasons that have been described in detail previously, we proposed an alternative nomenclature for the four major cholinergic cell groups in the basal forebrain.6 Accordingly, the cholinergic neurons within the medial septal nucleus were designated as Chl, those within the vertical limb nucleus of the diagonal band of Broca as Ch2, those within the horizontal limb nucleus of the diagonal band as Ch3 and those within the nucleus basalis of Meynert and associated cell groups as Ch4. Furthermore, we subdivided the very extensive Ch4 group into anteromedial (CMam), anterolateral (CMal), intermediate (Ch4i) and posterior (Ch4p) subsectors. Arendt et al. imply that the nucleus basalis collectively corresponds to Chl + Ch2 + Ch4. This is not entirely accurate; only Ch4 and its subsectors correspond to the traditional designation of nucleus basalis. Although most of the detail in our paper was focused on the brain of the monkey, we also specifically stated that identical Ch sectors could be identified in the human brain. In fact, we included photomicrographs of the human basal forebrain and indicated the putative location of Chl, Ch2, Ch3am, Ch4a1, and Ch4i.6 Arendt et al. follow this designation very closely and we agree with their labeling of the relevant forebrain cell groups according to the Ch nomenclature. However, there are some potential discrepancies in the way the topography of projections from Ch4 to cortical areas has been interpreted.
For example, we specified that CMam is a major source of cholinergic input only to the medial aspect of area 7, not to its dorsolateral parts. Arendt et al. assume a relationship between Ch4am and area 7 without specifying which part of area 7 was examined. Secondly, they imply a relationship between Ch4p and area 20 in the temporal lobe. However, our results had shown that Ch4p is the major source of cholinergic input only to the superior temporal gyrus (area 22) and the temporal pole (area 38). Area 20 which is more ventrally located in the temporal lobe would correspond to the projection area not of Ch4p but CMi (assuming, of course, that the projection patterns in man are topographically analogous to those in the monkey). With the exception of these two inconsistencies, the interpretation of the projection patterns of the other subsectors is essentially accurate. The authors state that their results support “the hypothesis of a cholinergic pathogenesis of neuritic plaques” (Ref. 3, p. 12). According to this position, plaques are largely due to degenerated cholinergic endings. Plaque density therefore reflects the extent of neuronal loss in the nucleus basalis. However, if the nucleus basalis (Ch4) is the primary site of predilection in Alzheimer’s disease and if the destruction of these neurons gives rise to plaques, then on average, areas with the least amount of intrinsic cholinergic innervation might be expected to have the least plaque density. In the monkey brain, we showed that association areas in prefrontal, posterior parietal and lateral temporal regions have the least amount of cholinergic innervation.’ Nonetheless, on average, these areas contain among the highest plaque counts in patients with Alzheimer’s disease.5 Primary sensory areas, on the other hand, despite a higher cholinergic innervation than association areas, have the least amount of plaques.5 Therefore, the relative intensity of cortical cholinergic innervation (as described in the monkey brain) does not appear to predict the selective regional vulnerability to the formation of plaques in Alzheimer’s disease. One way to reconcile this potential discrepancy is to accept a different hypothesis which is also acknowledged as a legitimate alternative by Arendt 215
276
\I-M.
and colleagues (Ref. 3. p. 12). According to this alternative, the primary pathology is in the cortex rather than in the nucleus basalis.‘,4.” In that case. the plaque density would simply reflect the severity of cortical involvement by the unknown pathogen. Cortical involvcmcnt could then give rise to sccondary retrograde or trans-synaptic degeneration within the cholinergic neurons of the basal forebrain. Since such secondary effects occur only along established neural pathways, the basal forebrain cell loss would bc most severe in the Ch sectors which project to the cortical areas that have the greatest plaque density (hence the most severe pathology). This expectation is consistent with the results of Arendt ct al. The hypothesis of a primary cortical pathology followed by secondary degeneration of subcortical neurons also provides a simple explanation for the rather puzzling fact that cholinergic neurons which do not project to cortex (such as those in the striatum) are spared in Alzheimer’s disease, whereas noncholinergic neurons with cortical projections (such as those in the brainstem rdphe and nucleus locus ceruleus) show degenerative changes. Another observation by Arendt et al. indicates that the neuronal count in the basal forebrain cholinergic cell groups is slightly higher in the right hemisphere than in the left. This deserves comment in view of the observation by Amaducci and colleagues that the temporal neocortex in the left hemisphere contains a higher level of choline acetyltransferase activity.’ Since choline acetyltransferase is a specific presynaptic marker for cholinergic innervation and since the major source of this innervation is in the basal forebrain, this finding might have led to the prediction that there would be more cortically projecting cholinergic neurons in the left hemisphere than in the right, especially since these cholinergic cells have almost no crossed cortical projections. The findings
MCSCL.AS~
by Arendt er al. clearly show that the asymmrtry 01’ cortical choline acetyltransferase. if confirmed by further studies. will need a different and probably more complex explanation. Let me conclude by stating that I found the paper by Arendt ef al.‘ very informative. Thanks to the detailed analysis that it provides, it is now possible to ask more quantitative questions which will hopefully become the focus of further investigations. REFERENCFS
1. Amaducci L., Sorbi S.. Albanese A. and Gainotti G.
2.
3.
4
5
(1981) Choline acetyltransferase (ChAT) activity differ in right and left human temporal lobes. Neurolr>gv 31, 799-805. Appel S. H. (1981) A unifying hypothesis for the cause of amyotrophic lateral sclerosis, parkinsonism and Alzheimer’s disease. Ann. Neurol. 10, 499-505. Arendt T., Bigl 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, I -14. Bloxam C. A., Perry E. K., Perry R. H. and Candy J. M. (1984) Neuropathological and neurochemical correlates of Alrheimer-type and parkinsonian dementia. In Alzheimer’s Disease: Advances in Basic Research and Therapies. (eds Wurtman R. J., Corkin S. H. and Growdon J. H.). pp. 39-52. Center for Brain Sciences and Metabolism Charitable Trust. Cambridge. Massachusetts. Kemper T. (1984) Neuroanatomical and neuropathological changes in normal aging and deme&a. In Clinical Neurolonv Aainn (ed. Albert M. L.). DD. 9-52. ’ ’’ Oxford University Press. New York. Mesulam M-M.. Mufson E. J., Levey A. I. and Wainer B. H. (1983) Choline@ innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus baaalis (substantia innominata) and hypothalamus in the rhesus monkey. J. camp. Neural. 214, 170-197. Mesulam M-M., Rosen A. D. and Mufson E. J. (1984) Regional variations in cortical cholinergic innervation: chemoarchitectonics of acetylcholinesterase-cantaining fibers in the macaque brain. Bruin Res. 311, 245-258. ..I
6
7
__.