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-hydroxyindoleacetic acid 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 { 11 challenged the view that the major ...
