LETTERS
Treatment Strategy for the Corticocortical Neuron Patholom of Alzheimer's Dis&e D. M. Bowen, FRCPath,' P. T. Francis, PhD,' A. W. Procter, MRCPsych,'? J. V. Halliwell, PhDJ D. M. A. Mann, MRCPath,§ and D. Neary, MD" Terry and colleagues [I) recently provided novel postmortem evidence that cortical synaptic pathology in Alzheimer's disease (AD) involved neurons other than cholinergic cells. DeKosky and Scheff (see {l}) and ourselves (e.g., see 121, also [I)) argued that a critical synaptic pathological change was degeneration of corticocortical neurons, based on living patients. This included analyses of tissue from neurosurgical craniotomies, where extent of this degeneration correlated with dementia rating (see also [ 1)).DeKosky and Scheff considered only the histopathology, without benefit of neurosurgical controls, yet drew the pessimistic conclusion that pharmacotherapy will not succeed. We also described the neurochemistry (e.g., relative sparing of dopamine, gammaaminobutyric acid, and somatostatin, as well as noradrenaline by most criteria) and considered the affected cortical neurons to be glutamatergic cells, in particular those in parietotemp o d areas. Thus it was proposed [2) that the glutamate partial agonist, Scycloserine, should be tested for clinical efficacy. Although this compound should facilitate the effect on the N-methyl-D-aspartate receptor complex of the remaining pool of transmitter glutamate, it is unlikely to affect responses of other subtypes of glutamate receptor. A new class of drug, the selective serotonin (5-HT) 1A receptor antagonist [e.g., 31, should facilitate all effects of the remaining glutamate transmitter pool by inhibiting the tonic hyperpolarizing action of endogenous 5-HT on pyramidal neurons {43, thereby compensating for reduced excitatory (glutamatergic) input caused by the degenerative process. The approach is also indicated because the 1A receptor seems enriched on the appropriate cell, neocortical pyramidal neurons {5) of layer I1 16). There is further support because even in autopsy AD brain half of the many cortical areas assayed had no evidence of a selective reduction in presynaptic 5-HT activity. AD is a slowly progressing disorder, so this deficiency is probably never a widespread feature. Indeed, those 5-HT nerve endings remaining appear most active in the most demented patients, based on the increased ratio of 5-hydroxyindoleacetic acid to 5-HT in many cortical tissues and 5-hydroxyindoleaceticacid concentration in lumbar CSF that positively correlated with dementia rating of histologically verified AD patients (see ref. 17 in [ 2 ] ) .It is well known that drugs showing 5-HT1, agonism reduce aggression and depression in animal models, so the proposed strategy will require careful evaluation. Corticocortical neurons are probably also subject to cholinergic modulation { 4 ) but no ideal (i.e., long lasting and nontoxic) acetylcholine esterase inhibitor has been tested with optimal methodology (e.g., no unequivocal diagnostic test for AD exists, other than by neurohistopathology). Indeed, the well-known and exaggerated original claim for tet-
rahydroaminoacridine has added further to the pessimism described above. Terry and associates { 11challenged the view that the major contributor to synaptic pathology is deposition of P-amyloid protein. This event has, however, provided the basis for many studies aimed at therapy by slowing progression of pathology. In conclusion, while approaches derived from studying trophic factors [I) and P-amyloid protein (as reviewed [2)) may eventually yield treatment to slow progression of the disease, drugs to affect neurotransmission will still be required for most patients to improve, if not reverse, functional disabilities already present and those that continue to evolve (albeit more slowly)--as well as for all sufferers during development of the alternative treatment.
'Miriam Marks Department of Neurochmistty Institute of Neurology London, UK t Department of Psychiat y United Medical and Dental School London, UK $Department of Physiology Royal Free Hospital School of Medicine London, U K $Department of Pathology liDepartment of Neurology Univeisity of Manchester Manchester, UK
References 1. Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572-580 2. Bowen DM, Francis PT,Procter AW, Young AB. Treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry 1992 (in press) 3. Bjork L, Cornfield LJ, Nelson DL, et al. Pharmacology of the novel 5-hydroxytryptamine 1A receptor antagonist (9-5fluoro-8-hydroxy-2-(dipropylamino)tetralin: inhibition of (R)-8hydroxy-2-(dipropylamino)tetralin-induced effects. J Pharmacol Exp Therap 1991;258:58-65 4. McCormick DA, Williamson A. Convergence and divergence of neurotransmitter action in human cerebral cortex. Proc Natl Acad Sci USA 1989;86:8098-8102 5. Pangalos MN, Francis PT, Middlemiss DN, et al. Selective destruction of a sub-population of cortical neurones by suicide transport of volkensin, a lectin from Adenia uolkensii. J Neurosci Meth 1991;40: 17-29 6. Pazos A, Probst A, PalaciosJM. Serotonin receptors in the human brain-111. Autoradiographic mapping of serotonin-1 receptors. Neuroscience 1987;2197- 122
Lhermitte-Duclos Disease and Cowden Disease: A Third Case Mark A. King, MBBS," Terence J. Coyne, FRACS,? Diane J. Spearritt, MBBS,S and Richard S . Boyle, FRACP' In the May issue of Annals, Padberg and colleagues reported on 2 individuals with both Lhermitte-Duclos disease and
112 Copyright 0 1992 by the American Neurological Association
Treatment Strategy for the Corticocortical Neuron Patholom of Alzheimer's Dis&e D. M. Bowen, FRCPath,' P. T. Francis, PhD,' A. W. Procter, MRCPsych,'? J. V. Halliwell, PhDJ D. M. A. Mann, MRCPath,§ and D. Neary, MD" Terry and colleagues [I) recently provided novel postmortem evidence that cortical synaptic pathology in Alzheimer's disease (AD) involved neurons other than cholinergic cells. DeKosky and Scheff (see {l}) and ourselves (e.g., see 121, also [I)) argued that a critical synaptic pathological change was degeneration of corticocortical neurons, based on living patients. This included analyses of tissue from neurosurgical craniotomies, where extent of this degeneration correlated with dementia rating (see also [ 1)).DeKosky and Scheff considered only the histopathology, without benefit of neurosurgical controls, yet drew the pessimistic conclusion that pharmacotherapy will not succeed. We also described the neurochemistry (e.g., relative sparing of dopamine, gammaaminobutyric acid, and somatostatin, as well as noradrenaline by most criteria) and considered the affected cortical neurons to be glutamatergic cells, in particular those in parietotemp o d areas. Thus it was proposed [2) that the glutamate partial agonist, Scycloserine, should be tested for clinical efficacy. Although this compound should facilitate the effect on the N-methyl-D-aspartate receptor complex of the remaining pool of transmitter glutamate, it is unlikely to affect responses of other subtypes of glutamate receptor. A new class of drug, the selective serotonin (5-HT) 1A receptor antagonist [e.g., 31, should facilitate all effects of the remaining glutamate transmitter pool by inhibiting the tonic hyperpolarizing action of endogenous 5-HT on pyramidal neurons {43, thereby compensating for reduced excitatory (glutamatergic) input caused by the degenerative process. The approach is also indicated because the 1A receptor seems enriched on the appropriate cell, neocortical pyramidal neurons {5) of layer I1 16). There is further support because even in autopsy AD brain half of the many cortical areas assayed had no evidence of a selective reduction in presynaptic 5-HT activity. AD is a slowly progressing disorder, so this deficiency is probably never a widespread feature. Indeed, those 5-HT nerve endings remaining appear most active in the most demented patients, based on the increased ratio of 5-hydroxyindoleacetic acid to 5-HT in many cortical tissues and 5-hydroxyindoleaceticacid concentration in lumbar CSF that positively correlated with dementia rating of histologically verified AD patients (see ref. 17 in [ 2 ] ) .It is well known that drugs showing 5-HT1, agonism reduce aggression and depression in animal models, so the proposed strategy will require careful evaluation. Corticocortical neurons are probably also subject to cholinergic modulation { 4 ) but no ideal (i.e., long lasting and nontoxic) acetylcholine esterase inhibitor has been tested with optimal methodology (e.g., no unequivocal diagnostic test for AD exists, other than by neurohistopathology). Indeed, the well-known and exaggerated original claim for tet-
rahydroaminoacridine has added further to the pessimism described above. Terry and associates { 11challenged the view that the major contributor to synaptic pathology is deposition of P-amyloid protein. This event has, however, provided the basis for many studies aimed at therapy by slowing progression of pathology. In conclusion, while approaches derived from studying trophic factors [I) and P-amyloid protein (as reviewed [2)) may eventually yield treatment to slow progression of the disease, drugs to affect neurotransmission will still be required for most patients to improve, if not reverse, functional disabilities already present and those that continue to evolve (albeit more slowly)--as well as for all sufferers during development of the alternative treatment.
'Miriam Marks Department of Neurochmistty Institute of Neurology London, UK t Department of Psychiat y United Medical and Dental School London, UK $Department of Physiology Royal Free Hospital School of Medicine London, U K $Department of Pathology liDepartment of Neurology Univeisity of Manchester Manchester, UK
References 1. Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572-580 2. Bowen DM, Francis PT,Procter AW, Young AB. Treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry 1992 (in press) 3. Bjork L, Cornfield LJ, Nelson DL, et al. Pharmacology of the novel 5-hydroxytryptamine 1A receptor antagonist (9-5fluoro-8-hydroxy-2-(dipropylamino)tetralin: inhibition of (R)-8hydroxy-2-(dipropylamino)tetralin-induced effects. J Pharmacol Exp Therap 1991;258:58-65 4. McCormick DA, Williamson A. Convergence and divergence of neurotransmitter action in human cerebral cortex. Proc Natl Acad Sci USA 1989;86:8098-8102 5. Pangalos MN, Francis PT, Middlemiss DN, et al. Selective destruction of a sub-population of cortical neurones by suicide transport of volkensin, a lectin from Adenia uolkensii. J Neurosci Meth 1991;40: 17-29 6. Pazos A, Probst A, PalaciosJM. Serotonin receptors in the human brain-111. Autoradiographic mapping of serotonin-1 receptors. Neuroscience 1987;2197- 122
Lhermitte-Duclos Disease and Cowden Disease: A Third Case Mark A. King, MBBS," Terence J. Coyne, FRACS,? Diane J. Spearritt, MBBS,S and Richard S . Boyle, FRACP' In the May issue of Annals, Padberg and colleagues reported on 2 individuals with both Lhermitte-Duclos disease and
112 Copyright 0 1992 by the American Neurological Association
