Arthur S. Kling

ORAL TETRAHYDROAMINOACRIDINE IN LONG-TERM TREATMENT OF SENILE DEMENTIA, ALZHEIMER TYPE

We treated 17 patients who had moderate to severe Alzheimers disease with oral tetrahydroaminoacridine (THA), a centrally active anticholinesterase, in a three-phase study. In the nonblinded first phase of the study, significant improvement occurred in subjects who received the drug, as compared with their pretreatment status, on the global assessment (P = 0.001), the Orientation Test (P = 0.001), and the more sophisticated Names Learning Test (P = 0.001). During the second phase, the subjects served as their own controls in a double-blind, placebo-controlled, cross-over study in which the order of administration of the drug and placebo was randomly assigned. Among the 14 subjects completing Phase II, THA treatment produced significantly better results than placebo on the global assessment (P = 0.003), the Orientation Test (P = 0.004), the Alzheimers Deficit Scale (P = 0.003), and the Names Learning Test (P = 0.001). Twelve subjects have entered Phase III, which involves long-term administration of oral THA. The average duration of treatment in these subjects at present is 12.6 months; symptomatic improvements have occurred, and no serious side effects attributable to THA have been observed. These encouraging initial results suggest that THA may be at least temporarily useful in the long-term palliative treatment of patients with Alzheimers disease. We stress that further observations will be required before a clear assessment of the role of this agent can be made.

Response of neurons in the macaque amygdala to complex social stimuli

The presence of neurons in macaque temporal cortex and amygdala which fire selectively in response to social stimuli has been demonstrated by several investigators. The extent to which such neuronal populations may respond to a broad range of social features, including expressive movements and interactions, has not been fully explored due to the difficulty of presenting such complex stimuli in a controlled fashion. We describe a method for presenting moving segments of macaque behavior, visual and auditory, to animal subjects during single unit recording. The method permits a broad range of stimuli to be used both as probes and as controls. In addition, a novel technique for monitoring eye position in alert macaque subjects is described. We present results from the medial amygdala and adjacent cortex, demonstrating that neurons in these regions respond selectively to features of the social environment.

Platelet glutathione peroxidase and monoamine oxidase activity in schizophrenics with CT scan abnormalities: relation to psychosocial variables

We have previously reported that the activity in platelets of the important antioxidant enzyme glutathione peroxidase (GPx) is inversely correlated with computed tomographic (CT) measures of brain atrophy in a population of patients with chronic schizophrenia, suggesting that low GPx may be a vulnerability factor in those schizophrenic patients with structural brain abnormalities. The significance of this finding has now been explored in a larger clinical population by examining the relation of GPx and CT parameters to psychosocial variables and to the activity of platelet monoamine oxidase (MAO), which has also been reported to be altered in certain schizophrenic populations. In the present study, low platelet GPx and high brain atrophy were found to be associated with DSM-III diagnoses of nonparanoid schizophrenia, a high degree of chronicity, and a predominance of negative symptoms. Contrary to some literature reports, atrophy also correlated with age and length of illness among the schizophrenic patients, although the contribution of these factors was less than that of low GPx, which was itself not age dependent. The ventricle-brain ratio (VBR) and atrophy were highly correlated in a control group of affective disorder patients, but not in the schizophrenic group, where large VBRs were found predominantly in the DSM-III undifferentiated subgroup. The low-GPx/high-atrophy schizophrenic patients had normal platelet MAO levels, and MAO was significantly lower only in the paranoid subgroup, consistent with reported observations. There was no evidence for a neuroleptic-induced effect on either enzyme.

Glutathione peroxidase and CT scan abnormalities in schizophrenia

The search for morphological clues to the etiology of schizophrenia has led to widespread application of computed tomography (CT) scans in the examination of patients. These investigations have resulted in numerous reports over the past several years of brain atrophy and increased ventricle-brain ratios (VBR), suggestive of neuronal tissue damage, associated with the disorder. Altered activity of cellular antioxidant systems have been implicated in the neuronal cell loss that is associated with degenerative diseases of the central nervous system (CNS), but this phenomenon has not been investigated with respect to functional disorders like schizophrenia. A search for such a relationship in schizophrenics with evidence of brain atrophy has been initiated by measuring the activity of the important antioxidant enzyme glutathione peroxidase (GPx) in blood samples from a population of chronic schizophrenics and age- and sex-matched nonschizophrenic mental patients as controls. A strong negative correlation has been found between GPx activity in both isolated platelets and erythrocytes and CT scan measures of brain atrophy and VBR in the schizophrenics, but not in the control population, which exhibited comparable CT scan abnormalities. These observations suggest a unique relationship of GPx to the mechanism of tissue damage in the schizophrenics.

Tacrine in the Treatment of Alzheimer’s Disease

The initial report of the effectiveness of tacrine or tetrahydroaminoacridine (THA) in the treatment of some patients with Alzheimers disease has been confirmed by further study of additional subjects and by preliminary reports from other investigators. The major side effect, elevation of liver enzymes, is shown to be reversible, dose-dependent and without significant hepatic pathology. Therapeutic serum concentrations of THA vary between 7 and 20 ng/ml. In addition to its presumed action as an acetylcholinesterase inhibitor, data are presented demonstrating marked effects on other brain neurotransmitters in animal models.

CT scans in sub-groups of chronic schizophrenics

Measurements of the ventricular brain ratio (VBR), width of the sylvian fissure, and symmetry of the frontal lobes were obtained from 26 chronic schizophrenic patients, 22 alcoholic and neurological patients, and 20 normal controls. All schizophrenic subjects were non-responsive to long-term neuroleptic medication for 3-25 yr and were between 23 and 45 yr of age. Detailed diagnostic workups differentiated two sub-groups by DSM III criteria, residual and paranoid. The former group was characterized by large VBRs while the paranoids were within the range of normal controls. Those patients with VBRs greater than nine had wider sylvian fissures and increased frequency of reversed frontal asymmetry. As a group, the VBRs of all schizophrenics differed significantly from normal controls but did not differ from those of alcoholics or patients with neurological disorders (migraine, generalized seizures). This finding indicates that DSM III criteria applied to CT scan measures may help define a sub-group within the schizophrenias. While not specific to this disorder, the underlying pathology demonstrating increased VBRs and other CT scan changes may be specific to but different from other disorders.

Isolation and the fluorometric, high-performance liquid chromatographic determination of tacrine

Tacrine (THA; 1,2,3,4-tetrahydro-9-aminoacridine) is an anticholinesterase agent which has been used clinically, most recently in the treatment of Alzheimer-type dementias. This paper describes the methodology for the isolation and quantitation of THA at therapeutic levels in serum from human subjects. Using C18 Bond Elut columns and an HPLC/fluorometry system, this assay exhibits a considerable improvement in sensitivity over previous uv methods, and allows routine testing of THA levels in serum samples of reasonable volume from human subjects.

Neurochemical correlates of the Klüver-Bucy syndrome by in vivo microdialysis in monkey

The Klüver-Bucy syndrome is a well known consequence of lesions of the temporal lobe, but the neural mechanisms remain obscure. To elucidate the neurochemical changes in this syndrome, we utilized in vivo microdialysis of amygdala and hypothalamus in two Cebus monkeys (C. apella) before and after bilateral lesions of the temporal pole (TP). Both subjects were housed and observed in a social group when not being dialyzed. Behavioral changes consequent to the TP lesion included early postoperative anorexia, adipsia, hunched posture, tameness, and lethargy. Subsequently loss of fear, hyperorality, loss of social rank, and social withdrawal were observed. Neurochemical changes in amygdala included fall in DA metabolites, increase in NE, and fall in 5-HIAA. The amino acids glutamate and aspartate were both lower postoperatively but more so in the subject with the greatest behavioral changes. Similar changes were noted in hypothalamus except for DA metabolites which remained unchanged. The Klüver-Bucy syndrome consequent to ablation of the temporal pole appears related to a partial deafferentation of excitatory projections to amygdala, along with a lowering of DA and 5-HIAA and an increase in NE.

Clinical course of adult metachromatic leukodystrophy presenting as schizophrenia. A report of two living cases in siblings.

Adult metachromatic leukodystrophy is a demyelinating disease due to an inherited lack of arylsulfatase A activity. The purpose of this paper is to present the characteristics of this disorder as they occurred chronologically in two siblings, prior to and subsequent to the appearance of gross neurological deficits. A deficit in spatial relationships, as contrasted with verbal abilities, was observed initially in both cases at age 13. Initial psychiatric symptoms were noted at age 16 and 18, with both patients being diagnosed subsequently as schizophrenic. Gross neurological deficits were observed 2 and 13 years, respectively, after the appearance of psychiatric symptoms. A deficit in spatial relationships may be a very sensitive early indicator of adult metachromatic leukodystrophy.

Slow wave changes in amygdala to visual, auditory, and social stimuli following lesions of the inferior temporal cortex in squirrel monkey (Saimiri sciureus)

Radiotelemetry of slow wave activity of the amygdala was recorded under a variety of conditions. Power, and the percentage of power in the delta band, increased in response to stimulation. Recordings of monkey vocalizations and slides of ethologically relevant, natural objects produced a greater increase in power than did control stimuli. The responses to auditory stimuli increased when these stimuli were presented in an unrestrained, group setting, yet the responses to the vocalizations remained greater than those following control stimuli. Both the natural auditory and visual stimuli produced a reliable hierarchy with regard to the magnitude of response. Following lesions of inferior temporal cortex, these two hierarchies are disrupted, especially in the auditory domain. Further, these same stimuli, when presented after the lesion, produced a decrease, rather than an increase, in power. Nevertheless, the power recorded from the natural stimuli was still greater than that recorded from control stimuli in that the former produced less of a decrease in power, following the lesion, than did the latter. These data, in conjunction with a parallel report on evoked potentials in the amygdala, before and after cortical lesions, lead us to conclude that sensory information, particularly auditory, available to the amygdala, following the lesion, is substantially the same, and that it is the interpretation of this information, by the amygdala, which is altered by the cortical lesion.