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Regional rather than global pathology decides symptoms in senile dementia of Alzheimer's type
Neurobiologyof Aging,Vol. 15, No. 3, pp. 367-368, 1994 Copyright© 1994ElsevierScienceLtd Printedin the USA. All fightsreserved 0197-4580/94$6.00 + .00
Pergamon 019"/-4580(94)F_,0005-K
COMMENTARY
Regional Rather Than Global Pathology Decides Symptoms in Senile Dementia of Alzheimer' s Type ARNE BRUN
Department of Pathology, Division of Neuropathology, University Hospital, S-221 85 LUND Sweden
REGEUR ET AL. find no global loss of neurons in the neocortex of patients with senile dementia of the Alzheimer type (SDAT). This is an important and provoking finding. It is important because it is arrived at with a new and more reliable method than those used before according to them. It is provoking because previous methods have shown a sometimes considerable loss of cells. Such a discrepancy may be explained by methodological differences. One should however also note that the study is limited to the neocortex in the senile form of Alzheimer's disease, which is generally accepted to be less intense than presenile Alzheimer's disease (PSDAT) in several aspects and a comparison with PSDAT might have yielded a different result though mostly on a regional basis. Also relevant is the duration of the disease not accounted for in this paper. In our experience those who escape intercurrent lethal diseases and survive to the end stage after a protracted course of 15 to 20 years reveal a severe neuronal loss and brain atrophy down to 6 to 700 g. The timepoint when a cell loss becomes obvious may be late in the course of the disease whereas in the early clinical stages and especially in the preclinical period such as in younger cases of Down's syndrome no neuronal loss and not even cortical atrophy is evident. Yet another explanation might be the finding that the neuronal loss involves mainly the larger neurons. This loss may at least in part be explained by neuronal atrophy causing the neurons to descend through the cell size classes and in the end hide in the glial size category particularly with older counting methods. Alzheimer's disease (AD) has often been named a global brain disorder, which is true in some respects. There are, however, important regional accentuations as shown by the symptomatological disease profile, the regional metabolic pattern, and neurochemical and pathoanatomical mainpoints of the disease process, in many respects with agreement between the results of these various methods of study. Particularly in the PSDAT but to some extent also in SDAT the regional focalization is evident. This refers in particular to the limbic areas not included in this study but also to basal temporal neocortex and parietal areas. In view of the nonglobal-neuronal-loss character of SDAT found in this study these regional accentuations make AD in essence a multi-regional brain disorder rather than a global one. The present paper under consideration reports in the occipital lobe an almost significant
loss of neurons which might have become significant had the calcarine-pericalcarine less involved areas not been included. Also the very mildly involved pre- and postcentral gyri would have had a similar effect on the outcome of the frontal and parietal lobe counts, respectively. The statement that "the estimate on total neuron number may overlook localized cell loss" hints at this regional pathology in a modest way. It is more clearly expressed in terms of reduction of cortical volume. This may be an effect of neuronal cell body atrophy but more of a loss of the connectivity apparatus as assumed in the discussion of the paper. These structures, comprising terminal neurites, dendrites with spinae and synapses make up a large proportion of the neuropil volume. The pathology of these structures has lately received increasing attention in the literature. Synapse loss correlates best with the symptoms of dementia (6) but may be global (5) though regionally accentuated especially in limbic areas (4). Synaptic pathology seems to be a common denominator for degenerative disorders such as AD, Parkinson's, and Huntington's diseases and frontal lobe degeneration of nonAlzheimer type (1) and also for prion disorders and alcohol encephalopathy, probably as a leading phenomenon (2,3,8). Currently, thus assuming a leading position in the discussion on the cause of dementia, synaptic loss may precede other pathologic changes in DAT being unrelated to the amyloid in terms of diffuse depositions (7). These depositions are by some regarded as the introductory step in the evolution of neuritic plaques. Synaptic loss may against this background be the basic change leading to an increasingly severe disconnection syndrome triggering the symptoms of dysfunction and hypometabolism. The degree of disconnection at that stage of the disease may be assumed to be far from total, why neuronal death and disappearance would not be necessary or even expected. The simultaneous or ensuing destruction of terminal neurites and dendrites can be expected to result in neuronal cell body atrophy, in countings of cell size classes giving the impression of loss of especially large neurons. This process might hypothetically evoke other changes such as plaques, tangles, and even amyloid, making them secondary or more of pathogenetic than etiological features. In view of the lack of such changes in degenerative and other conditions mentioned above and which are marked by synaptic loss, this chain of events may seem less likely, 367
368
BRUN
unless a genetic factor in SDAT, triggering or facilitating, makes up for the difference. In any event, the cause of the synaptic loss has become a central research issue. Returning to the neurons the logic end result would be a complete destruction of also the cell body maybe mainly in key areas with a more intense synaptic decline such as shown for the hippocampus (4). Such regional accentuations of the disease process may cause the main symptoms because focal even quite small lesions can produce dementia when strategically located, e.g., thalamic small symmetric infarcts. Neuronal loss in restricted though important areas would in accordance with the author's
statement hide in a global count. Their finding of no global cell loss focuses the attention on such key areas. Is SDAT, and in particular PSDAT, a global brain disease with accentuations in key areas where at least at not too advanced a stage the process can be reversed with restoration of neuronal connectivity, provided the scarring process does not hinder regrowth of neurites and dendrites, or is there a regional selective vulnerability where the Alzheimer process inevitably leads to cell death? Regional counts with the new method utilized by the authors, applied to such key areas and at different points of disease duration might provide an answer.
REFERENCES 1. Brun, A. Frontal lobe degeneration of non-Alzheimer type revisited. Dementia 126-131; 1993. 2. Clinton, J.; Forsyth, C.; Royston, M. C.; Roberts, G. W. Synaptic degeneration is the primary neuropathological feature in prion disease: A preliminary study. NeuroReport 4:65-68; 1993. 3. Freund, G.; Ballinger, W. E. Loss of synaptic receptors can precede morphological changes induced by alcoholism. Alcohol and Alcoholism. Suppi 1:385-391; 1991. 4. Honer, W. G.; Dickson, D. W.; Gleeson, J.; Davies, P. Regional synaptic pathology in AlzheimenSsdisease. Neurobiol. Aging 13:375-382; 1992. 5. Scheff, S. W.; Price, D. A. Synapse loss in the temporal lobe in Alzheimer's disease. Ann. Neurol. 33:190-199; 1993.
6. Terry D. R.; Masliah, E.; Salmon, D. P.; Butters, N.; De Teresa, R.; Hill, R.; Hansen, L. A. Katzman, R. Physical basis of cognitive alterations in Alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30:572-580; 1991. 7. Terry, R. D. The pathogenesis of Alzheimer's disease. What causes dementia? In: Christen et al. eds., Neurophilosophy and Alzheimer's disease. Springer-Verlag, Berlin, Heidelberg; 1992:123-130. 8. Zahn, S.-S.; Beyreuther, K.; Smitt, H. P. Quantitative assessment of the synaptophysin immuno-reactivity of the cortical neuropil in various neurodegenerative disorders with dementia. Dementia 4:66-74; 1993.
Pergamon 019"/-4580(94)F_,0005-K
COMMENTARY
Regional Rather Than Global Pathology Decides Symptoms in Senile Dementia of Alzheimer' s Type ARNE BRUN
Department of Pathology, Division of Neuropathology, University Hospital, S-221 85 LUND Sweden
REGEUR ET AL. find no global loss of neurons in the neocortex of patients with senile dementia of the Alzheimer type (SDAT). This is an important and provoking finding. It is important because it is arrived at with a new and more reliable method than those used before according to them. It is provoking because previous methods have shown a sometimes considerable loss of cells. Such a discrepancy may be explained by methodological differences. One should however also note that the study is limited to the neocortex in the senile form of Alzheimer's disease, which is generally accepted to be less intense than presenile Alzheimer's disease (PSDAT) in several aspects and a comparison with PSDAT might have yielded a different result though mostly on a regional basis. Also relevant is the duration of the disease not accounted for in this paper. In our experience those who escape intercurrent lethal diseases and survive to the end stage after a protracted course of 15 to 20 years reveal a severe neuronal loss and brain atrophy down to 6 to 700 g. The timepoint when a cell loss becomes obvious may be late in the course of the disease whereas in the early clinical stages and especially in the preclinical period such as in younger cases of Down's syndrome no neuronal loss and not even cortical atrophy is evident. Yet another explanation might be the finding that the neuronal loss involves mainly the larger neurons. This loss may at least in part be explained by neuronal atrophy causing the neurons to descend through the cell size classes and in the end hide in the glial size category particularly with older counting methods. Alzheimer's disease (AD) has often been named a global brain disorder, which is true in some respects. There are, however, important regional accentuations as shown by the symptomatological disease profile, the regional metabolic pattern, and neurochemical and pathoanatomical mainpoints of the disease process, in many respects with agreement between the results of these various methods of study. Particularly in the PSDAT but to some extent also in SDAT the regional focalization is evident. This refers in particular to the limbic areas not included in this study but also to basal temporal neocortex and parietal areas. In view of the nonglobal-neuronal-loss character of SDAT found in this study these regional accentuations make AD in essence a multi-regional brain disorder rather than a global one. The present paper under consideration reports in the occipital lobe an almost significant
loss of neurons which might have become significant had the calcarine-pericalcarine less involved areas not been included. Also the very mildly involved pre- and postcentral gyri would have had a similar effect on the outcome of the frontal and parietal lobe counts, respectively. The statement that "the estimate on total neuron number may overlook localized cell loss" hints at this regional pathology in a modest way. It is more clearly expressed in terms of reduction of cortical volume. This may be an effect of neuronal cell body atrophy but more of a loss of the connectivity apparatus as assumed in the discussion of the paper. These structures, comprising terminal neurites, dendrites with spinae and synapses make up a large proportion of the neuropil volume. The pathology of these structures has lately received increasing attention in the literature. Synapse loss correlates best with the symptoms of dementia (6) but may be global (5) though regionally accentuated especially in limbic areas (4). Synaptic pathology seems to be a common denominator for degenerative disorders such as AD, Parkinson's, and Huntington's diseases and frontal lobe degeneration of nonAlzheimer type (1) and also for prion disorders and alcohol encephalopathy, probably as a leading phenomenon (2,3,8). Currently, thus assuming a leading position in the discussion on the cause of dementia, synaptic loss may precede other pathologic changes in DAT being unrelated to the amyloid in terms of diffuse depositions (7). These depositions are by some regarded as the introductory step in the evolution of neuritic plaques. Synaptic loss may against this background be the basic change leading to an increasingly severe disconnection syndrome triggering the symptoms of dysfunction and hypometabolism. The degree of disconnection at that stage of the disease may be assumed to be far from total, why neuronal death and disappearance would not be necessary or even expected. The simultaneous or ensuing destruction of terminal neurites and dendrites can be expected to result in neuronal cell body atrophy, in countings of cell size classes giving the impression of loss of especially large neurons. This process might hypothetically evoke other changes such as plaques, tangles, and even amyloid, making them secondary or more of pathogenetic than etiological features. In view of the lack of such changes in degenerative and other conditions mentioned above and which are marked by synaptic loss, this chain of events may seem less likely, 367
368
BRUN
unless a genetic factor in SDAT, triggering or facilitating, makes up for the difference. In any event, the cause of the synaptic loss has become a central research issue. Returning to the neurons the logic end result would be a complete destruction of also the cell body maybe mainly in key areas with a more intense synaptic decline such as shown for the hippocampus (4). Such regional accentuations of the disease process may cause the main symptoms because focal even quite small lesions can produce dementia when strategically located, e.g., thalamic small symmetric infarcts. Neuronal loss in restricted though important areas would in accordance with the author's
statement hide in a global count. Their finding of no global cell loss focuses the attention on such key areas. Is SDAT, and in particular PSDAT, a global brain disease with accentuations in key areas where at least at not too advanced a stage the process can be reversed with restoration of neuronal connectivity, provided the scarring process does not hinder regrowth of neurites and dendrites, or is there a regional selective vulnerability where the Alzheimer process inevitably leads to cell death? Regional counts with the new method utilized by the authors, applied to such key areas and at different points of disease duration might provide an answer.
REFERENCES 1. Brun, A. Frontal lobe degeneration of non-Alzheimer type revisited. Dementia 126-131; 1993. 2. Clinton, J.; Forsyth, C.; Royston, M. C.; Roberts, G. W. Synaptic degeneration is the primary neuropathological feature in prion disease: A preliminary study. NeuroReport 4:65-68; 1993. 3. Freund, G.; Ballinger, W. E. Loss of synaptic receptors can precede morphological changes induced by alcoholism. Alcohol and Alcoholism. Suppi 1:385-391; 1991. 4. Honer, W. G.; Dickson, D. W.; Gleeson, J.; Davies, P. Regional synaptic pathology in AlzheimenSsdisease. Neurobiol. Aging 13:375-382; 1992. 5. Scheff, S. W.; Price, D. A. Synapse loss in the temporal lobe in Alzheimer's disease. Ann. Neurol. 33:190-199; 1993.
6. Terry D. R.; Masliah, E.; Salmon, D. P.; Butters, N.; De Teresa, R.; Hill, R.; Hansen, L. A. Katzman, R. Physical basis of cognitive alterations in Alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30:572-580; 1991. 7. Terry, R. D. The pathogenesis of Alzheimer's disease. What causes dementia? In: Christen et al. eds., Neurophilosophy and Alzheimer's disease. Springer-Verlag, Berlin, Heidelberg; 1992:123-130. 8. Zahn, S.-S.; Beyreuther, K.; Smitt, H. P. Quantitative assessment of the synaptophysin immuno-reactivity of the cortical neuropil in various neurodegenerative disorders with dementia. Dementia 4:66-74; 1993.