Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

https://science.sciencemag.org/content/sci/217/4558/408.full.pdf

The Cholinergic Hypothesis of Geriatric Memory Dysfunction

Cognitive decline associated with old age and consistent with the diagnosis of primary degenerative dementia is a unique clinical syndrome with characteristic phenomena and progression The authors describe a Global Deterioration Scale for the assessment of primary degenerative dementia and delineation of its stages The authors have used the Global Deterioration Scale successfully for more than 5 years and have validated it against behavioral, neuroanatomic, and neurophysiologic measures in patients with primary degenerative dementia

The Global Deterioration Scale for assessment of primary degenerative dementia.

Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N -methyl-D-aspartate subtype of excitatory amino acid receptor. Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. Conclusions: These data indicate that N -methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.

https://jamanetwork.com/journals/PSYCH/articlepdf/496531/archpsyc_51_3_004.pdf

Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.

Objective: Phencyclidine (PCP, “angel dust”) induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding ofschizophrenic pathophysiology. Methoc�: Twenty-five papers were identified that described the clinicaldose and serum and CSF levelsat which PCP induces its psychotomimetic effects. The dose range ofPCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. Results: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation ofits receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. Conclusions: These findings suggestthat endogenous dysfunction ofNMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models ofschizophrenia are discussedin relationship to the diagnosis and etiology of schizophrenia. (Am J Psychiatry1991;148:1301-1308)

Recent advances in the phencyclidine model of schizophrenia.

OBJECTIVE: The clinical hallmark of schizophrenia is psychosis. The objective of this overview is to link the neurobiology (brain), the phenomenological experience (mind), and pharmacological aspects of psychosis-in-schizophrenia into a unitary framework. METHOD: Current ideas regarding the neurobiology and phenomenology of psychosis and schizophrenia, the role of dopamine, and the mechanism of action of antipsychotic medication were integrated to develop this framework. RESULTS: A central role of dopamine is to mediate the “salience” of environmental events and internal representations. It is proposed that a dysregulated, hyperdopaminergic state, at a “brain” level of description and analysis, leads to an aberrant assignment of salience to the elements of one’s experience, at a “mind” level. Delusions are a cognitive effort by the patient to make sense of these aberrantly salient experiences, whereas hallucinations reflect a direct experience of the aberrant salience of internal representations. Antipsyc...

Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia.

As part of an investigation of the possible role of dopaminergic mechanisms in some psychoses, the behavioral effects of administration of l-Dopa to schizophrenic patients was assessed. l-Dopa was administered in dosages of 3–6 g/day to 10 such patients who had been maintained off neuroleptic drugs for approximately a week. Behavioral worsening occurred in all 10 patients. Three showed non-specific stimulation while the remaining 7 showed a combination of both stimulation and worsening of pre-existent symptoms or the development of new symptomatology. The significance of these findings is discussed with regard to those of other investigators.

Behavioral effects of L-dopa in schizophrenic patients.

The authors measured monoamine oxidase (MAO) activity in blood platelets of normal control subjects, patients with schizophrenia, and patients with other psychiatric diagnoses. No differences were ...

Blood platelet monoamine oxidase activity in psychiatric patients.

Both simple and disjunctive reaction times (RT) are known to slow with aging but there is a paucity of information on RT changes in senility. Since disjunctive RT involves cognition in addition to the sensory-motor speed and attentional components of simple RT, it was hypothesized that disjunctive RT would be a reliable index of age-related mental decline. To test this prediction, simple and disjunctive RT were measured in matched groups of 20 normal and 20 cognitively impaired elderly. Simple RT was slower in the senile patients than in the normal subjects, but this difference was accounted for by differences in disjunctive RT. The senile patients showed a much larger performance decrement with respect to disjunctive RT than did the normal subjects — a difference which was not accounted for by differences in simple RT. In a discriminant function analysis, disjunctive RT alone correctly identified the senile patients and the normal subjects with 86 percent accuracy. Thus, this measure proved to be a reliable index of age-related mental decline. Preliminary data indicate that disjunctive RT slowing is correlated with non-memory mental decline, and that poor performance is related to the need for care and supervision.

Reaction Time as a Diagnostic Measure in Senility

https://science.sciencemag.org/content/sci/205/4410/1039.full.pdf

Long-term choline treatment of memory-impaired elderly patients.

A gas chromatographic-mass spectrometric determination of blood N,N-dimethyltryptamine in normal controls and schizophrenic patients was carried out with a sensitivity limit of 0.05 ng/ml whole blood. Although the results appear to suggest that the mean DMT level was higher in the total patient group, those patients with acute psychosis, female patients and patients with suspiciousness scores on the BPRS of 4 or over, the differences were not statistically significant.

Dimethyltryptamine levels in blood of schizophrenic patients and control subjects

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