INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 8: 305-310 (1993)

AGE-ASSOCIATED MEMORY IMPAIRMENT: DIAGNOSTIC AND TREATMENT ISSUES

ANDREW BARKER* AND ROY JONES? *Research Fellow, ?Director, Research Institute for the Care of the Elderly, St Martin’s Hospital, Bath BA2 5RP, UK

SUMMARY There has been an enormous increase in research to identify potential pharmacological treatments for cognitive impairment in elderly people. Currently, well over 150 such compounds are under development by the pharmaceutical industry. However, among those who are potential targets for such treatment are many who suffer from relatively mild disorder, where the distinction from both dementia and ‘normality’ is not clear. These people include those described as suffering from benign senescent forgetfulness and age-associated memory impairment. This article discusses principles of diagnosis and treatment in this area with particular reference to age-associated memory impairment. For ethical, practical and economic reasons it is essential that these issues are examined thoroughly before any apparent breakthrough in therapy.

KEY WORDS-Ageing, diagnosis, treatment, cognitive impairment, age-associated memory impairment, benign senes- cent forgetfulness.

Developing effective treatments for significant cog- nitive impairment in elderly people is of major importance and an urgent necessity. The recent increased interest and activity in identifying poten- tial pharmacotherapy for these conditions (for example Crook, 1989; Crook et al., 1991; Eagger et al., 1991; Porsolt, 1989) is therefore encouraging. Well over 150 such compounds are currently under development by the pharmaceutical industry.

Among the diagnostic groups that are potential targets for treatment, the most obvious are the dementias, and cognitive impairments associated with cerebrovascular accidents. Although fully developed Alzheimer’s disease is relatively easy to identify compared to mild disorder, the diagnosis of early dementia is particularly challenging. How- ever, there are a large number of elderly people who may benefit from cognitive enhancement, where disease is even less well delineated and the border with normality is more blurred. This group includes those elsewhere described as suffering from very mild cognitive decline (Reisberg et al., 1982), limited cognitive disturbance (Gurland et al., 1982), mild cognitive impairment not amounting to dementia (WHO, 1978), and age-consistent memory impairment and late life forgetfulness (Blackford and La Rue, 1989). However, the most commonly used terms, which are the subject of this discussion, are benign senescent forgetfulness

0885-6230/93/040305-06$08.00 0 1993 by John Wiley & Sons, Ltd.

(BSF) (Kral, 1962), and more recently age-asso- ciated memory impairment (AAMI) (Crook et al., 1986).

BENIGN SENESCENT FORGETFULNESS

Kral (1958, 1962) described a form of intermittent impairment of memory retrieval in elderly residents in a retirement home as ‘benign senescent forgetful- ness’. It differed from a ‘malignant’ form in terms of its quality of symptoms, its milder severity, and its relatively non-progressive nature. He also identi- fied a ‘normal’ group but did not produce objective criteria to distinguish BSF from normality, and additionally described BSF as an expression of a ‘senium naturale’. The senescent forgetfulness groups were thus defined by comparison with an unimpaired peer group. He did not use formal cog- nitive testing to assess his patients. The subjects initially studied were residents of an old people’s home (Kral, 1958), many of whom had neurological signs (37.5% of those aged 60-80 years), whereas a further outcome study followed chronically insti- tutionalized psychiatric patients (Kral et al., 1964). Neither of these groups are representative of the general population. No distinction was made between those with chronic problems and those

Received 18 May 1992 Accepted 18 September 1992

306 A. BARKER AND R. JONES

with problems of recent onset. It is possible that many of these patients had long-standing cognitive impairment from a variety of causes (Spear Bassett and Folstein, 1991).

AGE-ASSOCIATED MEMORY IMPAIRMENT

The term ‘age-associated memory impairment, (AAMI) was proposed, with diagnostic criteria, in 1986 by a Work Group of the National Institute of Mental Health in the United States ‘to describe the memory loss that may occur in healthy, elderly individuals in the later decades of life’ (Crook et al., 1986). The authors aimed to distinguish the sufferers from those who experience no such loss and from those whose impairment is associated with other ‘specific’ disease states. To satisfy inclu- sion criteria, subjects must be over 50 years old and have complaints of gradual onset of memory loss for everyday events, adequate intellectual func- tioning, and memory performance more than one standard deviation below the mean for young adults. The diagnosis is excluded by any medical or neurological disorder, major psychiatric illness or drug consumption that may be responsible for the cognitive changes present.

The original paper outlined the well-documented age-related changes in memory which may occur in the absence of physical or neurological disease. The authors noted that even though these may be small in comparison with those seen in dementia, they undoubtedly are of great concern for some people, particularly those with intellectually demanding interests and occupations. Memory is involved in a number of everyday cognitive tasks such as problem-solving, concept formation and decision-making (Waugh and Barr, 1982). The work group recommended that recognition should be given to the distress that frequently lies behind complaints of memory loss and that effective treat- ments should be developed.

The prevalence of AAMI is unknown. Most of the published work on AAMI has been on highly selected samples of people of above average intelli- gence and educational background (Crook et al., 1990). One community study, using the AAMI inclusion criteria in a random sample of 67-77- year-olds, showed the prevalence to be 55.8% (Rei- nikainen et al., 1990). A second study, using most of the diagnostic criteria, showed AAMI to be pres-

ent in 49% of a group of over-55-year-olds, but they had previously been screened for the absence of relevant medical conditions (Smith et al., 1991). Although the true prevalence will thus be lower than the figures published, it is still likely to be a common disorder.

The original description of AAMI is confused both in the text and in the inclusion and exclusion criteria. The confusion is compounded by the lack of any discussion as to why these particular criteria were chosen. A principal difficulty is whether AAMI is describing a disease. Although diagnosis and treatment of AAMI is frequently mentioned, it is never referred to as a disease, which would normally be inextricably linked to diagnosis. Psy- chometric scores distinguishing AAMI from ‘pathologic’ memory loss have since been published (Crook, 1989), suggesting that AAMI is not patho- logic. It is not even clear whether AAMI aims to define the subgroup of elderly people with memory changes that are commonly seen in normal ageing, the subgroup who are distressed by these changes, or ‘to describe memory decline with age’ (Crook et al., 1986).

If the object is to describe memory decline with age, then it is not clear why the age limit for AAMI was set at 50. The paper acknowledges that the impairment is not necessarily qualitatively different from that which occurs in younger adults (and per- formance on some tests of new learning starts drop- ping from the twenties (Salthouse, 1982)). Is it reasonable to only recognize a disorder when the sufferer reaches a certain age?

Memory complaint is undefined, and it is not clear whether the work group really meant ‘com- plaint’ or ‘report’. The original paper describes AAMI as characterized by subjective evidence of memory loss, which does not necessarily imply complaint. A questionnaire (Larrabee et al., 1992) designed for the selection of people for drug studies in AAMI asks subjects to record how their memory performance has changed since high school or col- lege days on a number of tasks. Whether this consti- tutes a complaint or shows that the subject is in any way distressed by this change is doubtful. In other medical conditions, a patient’s distress or complaint may affect the decision to treat but is not normally a criterion for diagnosis. If it is included as an important element in diagnosis com- plications arise, because memory complaint is more closely correlated with depression than perform- ance (Bolla et al., 1991) and depressive symptoms are more frequent in elderly people (Gurland,

AGE-ASSOCIATED MEMORY IMPAIRMENT 307

1976). Although exclusion criteria for AAMI include depression as evidenced by a Hamilton Depression Rating Scale score of 13 or more, even mild depression may affect a person’s perception of their own performance (Bolla et al., 1991). In any case, the Hamilton Scale was designed for assessing the severity of illness in a patient already diagnosed as depressed rather than as a diagnostic instrument. Depressed patients do have problems remembering (Strack et al., 1985), but both memory complaints and objective memory performance improve with resolution of the depression (Stern- berg et al., 1976; Frith et al., 1983).

It is not clear why memory performance more than one standard deviation below the mean for young adults should be chosen as a criterion for inclusion. When developing normal or reference ranges it is more usual to consider values as abnor- mal if they are more than two standard deviations outside the mean for a population (Bland, 1987). It is thus even more inappropriate to use values only one standard deviation below the mean for a younger population; indeed, this part of the cri- teria would be satisfied by 16% of normal young adults. If the purpose of proposing the diagnosis is to describe an individual who has a decline in memory with age, then objectively it would be more appropriate to compare their present memory with an internal and retrospective measure of original cognitive functioning. Elderly people noticing a decline in memory do not compare their memory with the average young adult, but with their own previous performance. Tests have been developed for estimating preexisting IQ, and have been eva- luated in organic conditions (Crawford et al., 1988).

Cutoff scores for specific memory tests are given which are one standard deviation below the mean for young adults, but these scores have been changed in a subsequent publication without expla- nation (Crook, 1989). It is not clear what the signifi- cance is if one test result is below and two above the suggested cutoff score on different tests.

There is no discussion as to why adequate intel- lectual function is required for the diagnosis. The proposed method of indicating adequate intellec- tual function is by performance on the vocabulary subtest of the Wechsler Adult Intelligence Scale (WAIS). The WAIS is not referenced, though in a later publication reference is made to the 1955 version of the test (Wechsler, 1955) with no mention of the updated version (the WAIS-R) published in 1981 (Wechsler, 1981). The WAIS produces a ‘raw’

score that can be converted to a ‘scaled’ score, which compares the raw score to the mean perform- ance of a reference group of 20-34-year-olds. The inclusion criteria for AAMI provide a cutoff raw score and scaled score. However, the raw and scaled scores suggested do not equate in either version of the WAIS across the age range proposed, and it is unclear whether one or both scores should be met for inclusion. WAIS-R has revised tables for converting raw scores to scaled scores, and has been shown to yield IQs that are around half a standard deviation lower than the WAIS (Crawford et al., 1990).

The vocabulary subtest of the WAIS may have been chosen as a measure of original intellectual function because it correlates with overall intelli- gence and performance on it remains relatively stable with ageing (Wechsler, 1981). The scaled score cutoff proposed for adequate intelligence is just less than the mean for young adults, and since IQ is closely related to memory test performance, a memory test score more than one standard devi- ation below the mean for young adults might repre- sent a decline. However, the decline would only be recognized if intelligence started above ‘adequate intellectual function’ and memory deter- iorated to more than one standard deviation below the mean for young adults. People of lesser original intelligence could not therefore be described as suf- fering from the condition. Equally, those with an original level of intellectual functioning well above average, whose memory declined markedly with age but remained above the cutoff point for memory, would not be included by the diagnostic criteria. This may miss the group who would poten- tially be most distressed by the age-related decline.

A section in the working party’s report is devoted to the treatment or prevention of memory loss and suggests that there is a straightforward rationale for focusing clinical trials on the group of patients described by AAMI. This, combined with the lack of explanation for the diagnostic criteria chosen, has encouraged the suggestion that the criteria are most concerned with identifying healthy subjects for inclusion into drug trials for age-related cogni- tive impairments (Bamford and Caine, 1988).

CONCLUSION

Kral, in describing BSF, proposed the existence of a memory disorder that is not caused by a progress-

308 A. BARKER AND R. JONES

ive dementing illness and is distinct from normal ageing. Although a little work has been performed to operationalize the diagnosis (Blackford and La Rue, 1989), it is still uncertain whether there is such a disorder that does not represent long-standing deficit.

Discussion of whether AAMI exists or not is meaningless: it exists as it has been defined. Whether or not it is a ‘disease’ and can be ‘diag- nosed’ depends on the definitions one chooses. However, it is doubtful whether many doctors would consider AAMI a disease, as described, since it may occur in healthy people without risk to future health and because the diagnostic criteria make no attempt to separate AAMI from the changes of normal ageing. These issues may be less important than whether AAMI is a useful working concept for a group of people who would benefit from thera- peutic intervention.

In general medicine, often the only basis for a condition’s diagnosis and treatment is the presence of a significant deviation from the population norm where this has been shown to be associated with increased risk of morbidity. In certain conditions, such as deterioration in eyesight or hearing, doctors also intervene in distressing changes that may be seen as part of normal ageing, but clearly the use of pharmacological treatment for a relatively mild and low-risk disorder such as AAMI will only be tolerated by licensing authorities for drugs with very few side-effects.

An ethical difficulty still to be resolved is what the target level should be for improving function in the elderly. For instance, there has been the suggestion that growth hormone could be used in elderly people to restore a strong, lean body (Edi- torial, 1991) but, if accepted, this policy would have wide-ranging implications. If benefits were to out- weigh disadvantages, should elderly people dis- tressed by age-related changes be treated to a norm appropriate for their age, appropriate for young adults, or should the aim be to reverse any deterio- ration up to the level of the person’s original func- tion? This dilemma is central to the problems of classification in age-related cognitive impairment. Should sufferers be defined by comparison with their peer group, a young population, or an internal retrospective estimate of previous function? The suggestion from British workers (O’Brien and Levy, 1992) to return closer to Kral’s original for- mulation of BSF may indicate that views differ on opposite sides of the Atlantic as to what level of disorder requires medical intervention. However,

this suggestion would advocate returning towards a term which describes a much less specific popula- tion.

As it stands, the usefulness of the criteria for AAMI is minimized since the working party’s aims are confused and the reasoning behind the criteria it uses for definition is obscure. The working party has not achieved its probable objectives of identify- ing people in the later decades of life who exper- ience memory decline which is not associated with disease or related to drug ingestion. Indeed, the criteria may miss the group of people most dis- tressed by such a decline, and by making memory complaint an inclusion criterion it also suggests that people with a significant decline who do not complain do not have the condition.

There are many people who are greatly distressed by an age-related decline in memory which is not due to disease. If a treatment became available which was demonstrated to improve memory and had few significant side-effects, it would seem appropriate to help sufferers.

In order to demonstrate memory decline, the most appropriate objective comparison for current performance is the individual’s previous level of function. Although ideally this would be based on sequential memory tests starting in early adul- thood, in practice this information is unlikely to be available. Research is needed to describe how memory test performance changes with age in peo- ple with various levels of intelligence. When these data are available, it will be possible to estimate whether, and how much, a person’s memory has decreased by the combined use of several age and IQ standardized memory tests. It will also be poss- ible to estimate how much the person’s memory has declined in comparison with their peer group. Community studies with long-term follow-up will determine if there is a memory disorder which is distinct from dementia and from normal ageing, found in the absence of other recognized causes of memory impairment. Improving the diagnosis of early dementia is important in its own right, but will also assist in the delineation of age-related cognitive impairment.

The decision to treat someone whose memory has deteriorated will depend on a number of fac- tors. These will include deciding how much deterio- ration represents a significant loss, the level of distress experienced, and the patient’s wishes for treatment. Determining whether the distress is a cause or a result of the memory decline will need careful assessment.

AGE-ASSOCIATED MEMORY IMPAIRMENT 309

Further discussion is needed to consider what level of function we should be aiming for in elderly people, and an in-depth examination of the ethics of treating ‘normality’ in elderly people is required. Such considerations need to be addressed prior to any apparent breakthrough in drug treatment. This will ensure that any therapy, whether pharmacolo- gical o r non-pharmacological, is used appropria- tely.

REFERENCES

Bamford, K.A. and Caine, E.D. (1988) Does ‘benign senescent forgetfulness’ exist? Clin. Geriatr. Med. 4, 897-916.

Blackford, R.C. and La Rue, A. (1989) Criterion for diagnosing age associated memory impairment: Pro- posed improvements from the field. Development. Neuropsychol. 5,298-300.

Bland, M. (1987) An Introduction to Medical Statistics. Oxford University Press, Oxford.

Bolla, K.I., Lindgren, K.N., Bonaccorsy, C. and Bleeker, M.L. (1991) Memory complaints in older adults: Fact or fiction? Arch. Neurol, 48,61-64.

Crawford, J.R., Allan, K.M., Besson, J.A.O., Cochrane, R.H.B. and Stewart, L.E. (1990) A comparison of the WAIS and WAIS-R in matched UK samples. Brit. J . Clin. Psychol. 29, 105-109.

Crawford, J.R., Parker, D.M. and Besson, J.A. (1988) Estimation of premorbid intelligence in organic con- ditions. Brit. J. Psychiat. 153, 178-181.

Crook, T.H. (1989) Diagnosis and treatment of normal and pathologic memory impairment in later life. Semin. Neurol. 9,20-30.

Crook, T., Bartus, R.T., Ferris, S.H., Whitehouse, P., Cohen, G.D. and Gershon, S. (1986) Age-associated memory impairment: Proposed diagnostic criteria and measures of clinical change-report of a National Institute of Mental Health Work Group. Development. Neuropsychol. 2,261-276.

Crook, T.H., Johnson, B.A. and Larrabee, G.J. (1990) Evaluation of drugs in Alzheimer’s disease and age- associated memory impairment. In Methodology ofthe Evaluation of Psychotropic Drugs (0. Benkert, W. Maier and K. Rickels, Eds). Springer-Verlag, Berlin.

Crook, T.H., Tinklenberg, J., Yesavage, J., Petrie, W., Nunzi, M.G. and Massari, D.C. (1991) Effects of phos- phatidylserine in age-associated memory impairment. Neurology 41,644-649.

Eagger, S.A., Levy, R. and Sahakian, B.J. (1991) Tacrine in Alzheimer’s disease. Lancet 337,989-992.

Editorial (1991) Growth hormone therapy in elderly peo- ple. Lancet 337, 1131-1132.

Frith, C.D., Stevens, M., Johnstone, E.C. et al. (1983) Effects of ECT and depression on various aspects of memory. Brit. J. Psychiat. 142,61&617.

Gurland, B. J. (1976) The comparative frequency of depression in various adult age groups. J. Gerontol.

Gurland, B. J., Copeland, J. R. M., Kuriansky, J., Kel- leher, A., Sharpe, L. and Dean, L.L. (1982) The Mind and Mood of Aging. Mental Health Problems of the Community Elderly in New York and London. Croom Helm, Beckenham.

Kral, V.A. (1958) Neuro-psychiatric observations in an old people’s home. J. Gerontol. 13, 169-176.

Kral, V.A. (1962) Senescent forgetfulness: Benign and malignant. Can. Med. Assoc. J. 86,257-260.

Kral, V.A., Cahn, C. and Mueller, H. (1964) Senescent memory impairment and its relation to the general health of the aging individual. J. Am. Geriatr. SOC.

Larrabee, G.J., McEntee, W.J. and Crook, T.H. (1992) Age-associated memory impairment. In Cognitive Dis- orders: Pathophysiology and Treatment (L. J. Thal, W. H. Moos and E. R. Gamzu, Eds). Marcel Dekker, New York.

O’Brien, J. and Levy, R. (1992) Age associated memory impairment: Too broad an entity to justify drug treat- ment yet. Brit. Med. J. 304, 56.

Porsolt, R.D. (1989) The silent epidemic: The search for treatment of age-related memory impairment. Trends Pharmacol. Sci. 10,3-6.

Reinikainen, K. J., Koivisto, K., Mykkanen, L. et a/ . (1 990) Age-associated memory impairment in aged population: An epidemiological study. Neurology 40 (suppl. I), 177.

Reisberg, B., Ferris, S.H., De Leon, M.J. and Crook, T. (1982) The global deterioration scale for assessment of primary degenerative dementia. Am. J. Psychiat. 139, 1 1361 139.

Salthouse, T.A. (1982) Adult Cognition: An Experimental Psychology of Human Aging. Springer-Verlag, New York.

Smith, G., Ivnik, R.J., Petersen, R.C., Malec, J.F., Kok- men, E. and Tangalos, E. (1991) Age-associated memory impairment diagnoses: problems of reliability and concerns for terminology. Psychol. Aging 6, 551- 558.

Spear Bassett, S. and Folstein, M.F. (1991) Cognitive impairment and functional disability in the absence of psychiatric diagnosis. Psychol. Med. 21, 77-84.

Sternberg, D.E., Murray, M.D. and Jarvik, E. (1976) Memory functions in depression: Improvement with antidepressant medication. Arch. Gen. Psychiat. 33,

Strack, S., Blaney, P.H., Ganellen, R. J. and Coyne, J.C. (1 985) Pessimistic self-preoccupation, performance deficits, and depression. J. Pers. SOC. Psychol. 49, 1076-1085.

31,283-292.

12,101-1 13.

219-224.

310 A. BARKER AND R. JONES

Waugh, N.C. and Barr, R.A. (1982) Encoding deficits Revised, Manual. Psychological Corporation, San Antonio.

World Health Organisation (1 978) Mental Disorders: Glossary and Guide to their Classification in Accordance with the Ninth Revision of the International Classijica- tion of Diseases. WHO, Geneva.

in aging. In Aging and Cognitive Processes (F.I.M. Craik and S. Trehub, Eds). Plenum, New York.

Wechsler, D. (1955) Wechsler Adult Intelligence Scale, Manual. Psychological Corporation, New York.

Wechsler, D. (1981) Wechsler Adult Intelligence Scale-