Vasopressin treatment of cognitive dysfunction un progressive dementia

Life Sciences, Vol. 29, pp. 2721-2726 Printed in the U.S.A.

Pergamon Press

VASOPRESSIN TREAMENT OF COGNITIVE DYSFUNCTION IN PROGRESSIVE DEMENTIA

Herbert Weingartner Walter Kaye Philip Gold Sheila Smallberg Ron Peterson J.C. Gillin Michael Ebert

Laboratory of Psychology and Psychopathology National Institute of Mental Health Building 31, Room 4C-35 Bethesda, Maryland 20205 (Received in final form November 2, 1981) Summa ry Progressive dementia patients demonstrate profound and obvious learning-memory impairments. To a large extent, these are determined by failures to access and use previously learned knowledge (semantic memory) to affect encoding and processing of ongoing events (episodic memory). There are other forms of memory failures in man that are likely to be determined by quite different psychobiological mechanisms, such as failures to retain or consolidate information in memory. One important way in which drug treatments may facilitate the learning-memory impairment in mildly demented patients is by making semantic memory structures more accessible. Patients treated with l-desoamino-8-D-arginine vasopressin (DDAVP), a synthetic analog of the hypothalmic peptide arginine vasopressin, demonstrate cognitive enhancement by facilitating access to semantic memory structures that are part of long-term memory. It is generally accepted that integrative communication within the central nervous system proceeds not only by classical transynaptic-neurotransmission, but also by the interaction between brain and peptide hormones synthesized by the endocrine hypothalamus. These peptides are transported to disparate brain regions by axon transport, local blood stream circuits, or the cerebrospinal fluid. One of these hypothalamic hormones, arginine vasopressin (AVP), as well as several synaptic analogs of AVP, has been shown to enhance memory consolidation in both vasopressin-deficient rats and in intact animals (1-4). Recent studies in humans have shown that one of these vasopressin analogs, l-desamino-8-D-arginine vasopressin (DDAVP), can produce enhancements in learning and memory in cognitively impaired (depressed patients) and unimpaired healthy volunteers (5-6). A number of other single case studies have reported, with conflicting results, on the effects of AVP, or its analogs, in reversing dementia or amnesias (7-11). This paper reports on a study of the cognitive effects of DDAVP in a small, but homogeneous group of patients with progressive idiopathic dementia. Patients who were asked to volunteer for this study were carefully evaluated and selected only if they were in an early stage of a progressive dementia (PD). They were treated several times with either DDAVP 0024-3205/81/262721-06502.00/0

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or placebo, in a randomized cross-over design. Cognitive procedures, specifically designed to evaluate those components of information processing which appear to determine the memory-learning impairment of these types of patients (12), were used to assess DDAVP effects. Unlike many forms of amnesia, the PD patient is unable to effectively access previously learned knowledge structures in memory (semantic memory). For example, Korsakoff's disease patients also demonstrate profound memory impairments but can learn and remember procedures (13) because they can access previously acquired knowledge effectively. In PD patients, inability to access semantic memory results in incomplete encoding and superficial processing of ongoing events (12); consequently, failures appear in recent memory. Based on recent findings demonstrating cognitive effects of DDAVP in unimpaired subjects, it was predicted that such treatment might facilitate cognitive processes in PD patients where one of the reasons why memory-learning fails is due to inaccessibility of semantic memory structures leading to disrupted encoding processes. During the past several years, investigators have tested the efficacy of cholinerglc drug treatments, cholinergic agonists, and acethylcoholinesterase inhibitors, in affecting changes in the cognitive dysfunctions in PD patients. The logic of these experiments and clinical trials was based on the pattern of neurochemical and neuroanatomical findings in progressive dementias (14-21), as well as the reported facilitation of memory in unimpaired subjects treated with cholinergic agonists (22-3). These drugs, that stimulate cholinergic activity have been shown to produce some positive cognitive effects (24-27). While cholinergic and acethylcholinesterase inhibitor treaments will continue to be evaluated in PD patients, other types of treatment may also prove useful. One such form of treatment may consist of various neuropeptides that have been shown to stimulate cognitive processes. It is also clear that much additional study is required before we will fully appreciate the mechanisms of cognitive failure in PD or how cognition is altered by various modes of treatment. Methods In this study, seven carefully screened, early-stage progressive idiopathic dementia patients were evaluated on the basis of detailed neurological examinations, psychometrics, intelligence tests, neuropsychological tests, and with the use of laboratory tests and procedures previously developed to measure components of cognition learning and memory (12). All the patients studied demonstrated clear and extensive memory impairments (based on their Wechsler Memory Scale Scores in comparison to present and past IQ), but all were still quite capable of performing most daily activities without close supervision. All were employed up until no more than one year prior to their present evaluation. Clinical evaluation included at least two independent neurological and psychiatric examinations. Patients were not selected if any evidence appeared of multl-infarct dementia or a depression-related pseudo-dementia. Only patients whose history would be consistent with an Alzheimer's type of dementia (confirmable only on the basis of neuropathological findings) were included in the study. On present examinations, patients demonstrated above normal range performance on at least one of the Wechsler Adult Intelligence subtests. An estimate of patient's premorbid intelligence was also obtained by using weighted factors, including patient's age, sex, race, education, and occupation (28). Using these factors to estimate IQ, the premorbid IQs of these patients were all above average. After an evaluation period and practice with a series of laboratory procedures of memory and learning, patients were treated several times with DDAVP (in doses of from 30 to 60 ~g, administered in a double blind design. Each subject was administered a placebo at least three times, as well as varying doses of DDAVP as described in Table i. Drug and placebo treatment trials were introduced only after subjects had practiced both of the cognitive tasks described

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below (using equivalent forms of these procedures) and had demonstrated a stable performance on these tests. Cognition was always tested in the morning and one hour after placebo or DDAVP administration. The number of DDAVP administration. The number of DDAVP treatments each patient received on separate days during the course of the experiment is also described in Table I. TABLE 1 Characteristics of Progressive Dementia Patients and DDAVP Treatments Administered Patients Age

Sex I

Occupation

(WMS) 2

Drug Doses Tested in ~g

52

M

Executive

72.5

10-20-40

2

64

F

Executive Assistant

92

20

3

60

M

Business Executive

89.5

20-40-60

4

60

M

Physician

86.5

10-30-60

57

M

Ph.D. Music

57

10-20-40

65

M

Business Executive

79

10-20-40

60

M

Ph.D. Physics

59.5

10-20-40

IM= male F= female

2WMS= Wechsler Memory Score Generally, the W-MS should correspond to the full-scale IQ. All of the patients studied tended to have IQs in the superior range (above 120).

The cognitive tests used to assess the effects of DDAVP on cognition were designed to be simple, short, repeatable (using equivalent forms), and useful measures of: (I) access to semantic-memory structures and (2) learning and memory. It was predicted that if a treatment would facilitate cognitive processing in these patients, it would do so by making prior learning more available. A simple, but useful strategy for measuring accessibility to semantic memory structures is to ask subjects to freely associate, generate items, in response to stimuli that represent categories of information whose structure is known (29) or to search memory by generating words all starting with the same letter of the alphabet. On each testing session, two different letters and two different categories of information (e.g., vegetables, flowers) were used as stimuli. Subjects thought of as many words as possible in 90 seconds, following the presentation of each stimulus. Using this technique, it has been possible to show that inaccessibility to structures in memory is directly related to the memory-learning deficits associated with progressive dementia (12), but not predictive of many other forms of memory-learning failure (e.g., such as in depression)(30). Learning and recall were tested by asking subjects to listen to different but equivalent lists of 32 random words

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(controlled for word frequency in the language)(31), as well as imagery value (32). Recall was evaluated after a one-minute activity-filled delay period. This procedure was used in previous studies of similarly impaired early-stage dementia patients, as well as less cognitively impaired depressed patients. Using this kind of procedure~ as well as others, it has been possible to show that the forms of cognitive failures apparent in depression, dementia, and amnestic syndromes are quite different (12,30). This task was accomplished with some difficulty by these patients, but they could demonstrate some learning and memory. In addition, this same procedure has been useful in testing comparison population of unimpaired controls, as well as patients with other forms of cognitive failures. In evaluating cognitive performance of each patient, on both of these tasks, each patient's performance is described as the average for placebo and active drug conditions, and his average performance was used as a basis for contrasting the cognitive performance following DDAVP and placebo treatment. Results Following DDAVP treatment, PD patients were better able to generate appropriate responses to words and letters, (F(I,6) = 18.3; p < .005). These responses were all appropriate, given the nature of the category or letter used as a stimulus. This effect was most noticeable for the words generated during the last 60 seconds, rather than the more common or superficial responses that were produced during the first 30 seconds after stimulus presentation (see FIG. I). Unlike normal controls and regardless of treatment condition, patients were more productive in responding to letters than categories of information (F(I,6) = 6.24; p < .05), although DDAVP facilitated production of both types of responses. These findings suggest that DDAVP treatment helped facilitate access to semantic memory. Although there was some evidence that free recall performance was enhanced in some patients after DDAVP treatment, this effect was not statistically reliable for the entire group of seven patients; DDAVP mean recall = 6.1 words (standard error = 4.5); placebo mean free recall = 4.6 words (standard error = 2.1). Free recall of this information following placebo treatment was substantially less than that of cognitively impaired depressed patients and comparable to previously studied progressive idiopathic dementia patients (12,22). Fairly large intersubject variability appeared in free recall performance following DDAVP treatment with some patients demonstrating a clear response (facilitation of learning and memory), while others appeared unaided by DDAVP treatment. However, it was also apparent that those patients who demonstrated better facility in searching semantic memory, as measured by productivity in responding to letters and words after DDAVP treatment, tended to be the same patients who demonstrated an enhancement of their free recall performance (r = .79; p < .02). On the basis of these preliminary findings, DDAVP appears to facilitate cognitive performance in some progressive dementia patients. These changes in cognition appear mediated by increased facility for searching memory for semantic structures, which then results in more effective encoding of ongoing events, and therefore results in improvements in learning and memory. Memory impairments in man can be determined by a variety of mechanisms. Many forms result from failures to consolidate memory traces without associated dementia-like symptoms, expressed as an inability to access structures and knowledge stored in long-term memory (e.g., as in Korsakoff's syndrome). In contrast, in the progressive dementias, memory-learning failures appear related to the severity of the dementia. Memory-learning impairments appear related to failures to find structures and information in semantic memory. Treatments

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that may facilitate learning and memory in progressive dementias may do so through different mechanisms than those that would effect cognitive changes in other patient groups. In addition, the potential effectiveness of altering vasopressin activity or other treatments in dementia may be limited to a narrow therapeutic dose range, and to less demented patients, such as those in early, rather than late stages of a dementia. Clearly, much more must be learned about how various forms of treatments alter cognitive processes and the psychobiological mechanisms of forms of cognitive failures in man before effective and reliable remediation strategies are available.

Letters as Stimuli 6.5

Categories as Stimuli =

= DDAVP

o- - - o Placebo 6.0

5.5

09 LLI 09 Z O O. co uJ t~

LL

O

I

5.0

\-

4.5-

4.0-

-I

\\I

0E I.IJ

m

-

3.5z

\

\\

3.0-

2.5-

2.00

I 3O

I 6O

I 90

30

60

90

TIME

FIG. i Production of word associations to letters and categories of information following placebo and DDAVP treatment in progressive idiopathic dementia patients.

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i. 2. 3. 4. 5. 6. 7. 8. 9. i0. Ii. 12. 13. 14. 15.

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