The Transition from Normal Functioning to Dementia in the Aging Population

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LAURA FRATIGLIONI, BRENT SMALL, BENGT WINBLAD AND LARS BACKMAN

INTRODUCTION

During the last few decades a substantial effort has been made to understand better the etiology and natural history of dementia, which has led to significant results. However, only in recent years has the availability of follow-up data from several community-based studies provided us with the opportunity to explore what happens just before the manifestation of the first dementia symptoms and before the diagnosis of dementia. Most of the studies focused on Alzheimer's disease (AD). The preclinical phase of AD may be considered as the transition from normal aging to dementia.

COGNITIVE FUNCTIONING AND AGING

Backman et al. (1999) in a recent review on cognitive functioning in old age concluded that there is a rather global deterioration of cognitive functioning in old age. For some cognitive abilities (e.g. fluid intelligence, episodic memory, and working memory), the onset of decline occurs relatively early and continues into late life; for other abilities (e.g. crystallized intelligence and semantic memory), noticeable decline may not be evident until late adulthood. However, from the mid-70s of life and onward the magnitude of age-related decline appears to be quite similar across different forms of memory and cognition, with only two exceptions: primary memory and implicit memory. For these forms of memory, relative preservation appears to be the empirical rule, even in very old age. Given this scenario, the main challenge is to understand which specific changes in cognition are involved in the initial phases of AD, and to describe the timing and evolution of these changes.

Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics. Edited by K. Iqbal, S. S. Sisodia & B. Winblad. © 2001 John Wiley & Sons, Ltd.

TIME BEFORE DEMENTIA DIAGNOSIS

Due to the insidious onset of AD, the time of diagnosis is the only definite point in the initial phase of the disease. The time of diagnosis may be defined as the time when diagnostic criteria for dementia and AD are fulfilled. This time may be affected by several factors, including cultural, social, and medical conditions.

The studies conducted so far have focused on early clinical phases, which correspond approximately to 1-2 years before or after diagnosis, and on the preclinical phase, defined as occurring more than 2 years before diagnosis. This review summarizes the results from numerous studies aimed at describing cognitive performance in subjects before AD diagnosis.

COGNITIVE CHANGES IN THE INITIAL PHASES OF DEMENTIA

Even early in the disease process, AD patients typically exhibit deficits across multiple cognitive domains, including attention, memory, verbal ability, visuospatial skill, problem solving, and reasoning (Small et al., 1998). However, it is clear that the largest and most consistent cognitive deficit in early clinical AD is seen within the domain of memory. No form of memory is completely spared from the negative effects of AD (Almqvist, 1996).

Despite the involvement of all forms of memory even in the early phase and mild form of AD, numerous studies have consistently reported the presence of marked deficits in episodic memory in contrast with mild-moderate involvement of other cognitive functions (Almqvist et al., 1996). Episodic memory tasks, which involve conscious retrieval of information acquired in a particular place and a particular time, emerged as the tasks distinguishing most effectively between the normal old person and the patient with mild AD (Herlitz et al., 1995).

CHARACTERIZATION AND EVOLUTION OF COGNITIVE DEFICITS IN PRECLINICAL AD

Most of the studies addressing this topic followed a group of non-demented older persons across a time period of 2-4 years, to detect newly developed AD (incident cases). The cognitive performance at baseline in these incident AD cases was compared to the test results of those subjects who remained non-demented during the risk period. Numerous investigations are based on 2-4 years of follow-up. Few studies have explored a longer period, and even fewer reports tried to characterize the nature of the differences in cognitive performance between preclinical AD and non-demented subjects. Finally, only one study described the course of cognitive deficits in the preclinical phase of AD. The main findings from these three research lines will be discussed here.

COGNITIVE DEFICITS 2-4 YEARS BEFORE AD DIAGNOSIS

All studies consistently report a clear lowering of cognitive performance among incident AD cases some years before actual diagnosis. Such preclinical deficits in AD have been demonstrated in studies employing global indicators of cognitive performance (Aronson et al., 1990; Yoshitake et al., 1995; Small et al., 1997a). Deficits in specific cognitive abilities have been associated with the subsequent development of AD in one or more studies (Table 1.1). As is true in early clinical AD, the largest and most consistent cognitive deficits are observed within the domain of episodic memory. Small et al. (1997b) found that subjects who would develop AD across three-year follow-up had lower cognitive performance in a variety of tasks, including those assessing not only episodic memory, but also visuoperceptive skill, visuoconstructive skill, letter fluency, and category fluency. However, when all measures were entered into a logistic regression analysis, the tasks assessing episodic memory were found to dominate the prediction model.

The episodic memory deficit in persons who will develop AD appears to be highly generalizable across different materials and testing conditions (Backman et al., 1999). However, it may still be the case that some tasks are more effective than others in predicting future development of AD. Backman and Small (1998) examined the effect of cognitive support on the results of memory tasks in preclinical AD. Four different tasks that varied systematically with regard to the degree of cognitive support (more study time, organizability, and semantic retrieval cues) were administered. As expected, the incident AD cases showed a clear performance deficit at baseline (three years before diagnosis) but the same qualitative pattern as the controls, with performance gradually increasing across increasing levels of cognitive support. However, at the time of diagnosis, the incident AD cases failed to benefit from more study time and organizability in the free recall test,

Table 1.1. Cognitive deficits in preclinical Alzheimer's disease 2-4 years before diagnosis

Impaired function

Reference

Abstract reasoning

Jacobs et al., 1995; Fabrigoule et al., 1996

Episodic memory

Small et al., 1997b; Hodges et al., 1998; Grober et al., 2000

New learning

Grober and Kawas, 1997

Psychomotor speed

Masur et al., 1994

Verbal ability

Small et al., 1997b; Dartigues et al., 1997; Howieson et al.,

1997

Visuospatial skill

Small et al., 1997b

whereas performance gains were observed only in the most supportive condition. The authors suggested that a general impairment of episodic memory may precede reductions in cognitive reserve capacity in the early development of AD.

COGNITIVE DEFICITS 5+ YEARS BEFORE AD DIAGNOSIS

Table 1.2 reports the most recent studies that examined cognitive performance in preclinical AD over a period of more than 5 years before diagnosis. Using the data from the Framingham study, Elias et al. (2000) extended the surveillance period from 13 to 22 years for the subjects initially followed up by Linn et al. (1995). Due to this extension, test results of subjects developing AD at least ten years later were compared with the results from non-demented subjects. Lower scores for measures of new learning, recall, retention, and abstract reasoning obtained during a dementia-free period were associated with the development of AD. Lower scores for measures of abstract reasoning and retention predicted AD after a dementiafree period of ten years.

In the Kungsholmen Project, persons were assessed on three occasions over six years. On the last occasions, some individuals were diagnosed with AD (incident cases), although the entire study sample was non-demented at the first two measurement times. The cognitive assessment of the whole cohort was restricted to the Mini-Mental State Examination (MMSE) (Folstein et al., 1975), which is a global screening instrument for cognitive dysfunction. This instrument assesses multiple cognitive abilities, including orientation as to time and place, immediate and delayed word recall, naming, verbal repetition, reading, writing, and spatial ability. At both preclinical measurement points (six and three years before diagnosis), the incident AD cases showed deficits on one item only, namely delayed recall (Small et al., 2000). This result supports the view that the earliest cognitive deficits in AD are seen within the domain of episodic memory.

Table 1.2. Cognitive deficits in preclinical Alzheimer's disease 5 years or more before diagnosis

Impaired function

Time before diagnosis

The Framingham Study

Abstract reasoning

At least 5 years

Linn et al., 1995; Elias et

Attention

al., 2000

Retention of information

Verbal memory

The Kungsholmen Project

Delayed recall

4-7 years

Small et al., 2000;

Free recall

Backman et al., 2001

Recognition

A more recent study from the same project (Backman et al., 2001) reported the results from a comprehensive neuropsychological battery administered to a sample of the entire Kungsholmen Project's cohort. This sample was examined three times during a follow-up period of six years. The incident AD cases already showed clear deficits in the episodic memory tests (free recall and recognition) six years before diagnosis.

COURSE OF THE COGNITIVE IMPAIRMENT IN PRECLINICAL AD

Two studies from the Kungsholmen Project have addressed the issue of cognitive impairment in preclinical AD (Small et al., 2000; Backman et al., 2001). When the MMSE subitems were used in the whole cohort, the subjects in a preclinical phase of AD showed deficits in delayed recall function at both preclinical measurement points, but they did not exhibit selective decline between the six-year and the three-year point before diagnosis compared to the non-demented subjects. However during the last three years preceding the diagnosis, a precipitous decline was detected in delayed recall and across most cognitive domains assessed in the MMSE.

When results from the neuropsychological battery were examined during the six years of follow-up (Backman et al., 2001), performance in recognition and recall tests of subjects in preclinical AD, although lower than in non-demented subjects, remained pretty stable during the first three years of follow-up. The data suggest that the episodic memory deficit in preclinical AD is characterized by an early onset followed by relative stability, at least until a few years before a diagnosis may be rendered.

IDENTIFICATION OF SUBJECTS WITH PRECLINICAL AD

The results from the Kungsholmen Project suggest that AD is associated with a long preclinical period during which episodic memory deficits are detectable, although accelerated decline in performance may not be seen until the time period preceding diagnosis. Three main questions arise from these data:

1. Are the deficits in episodic memory detected in subjects who later develop AD present throughout their life, or was there a time when these subjects performed as well as people who do not develop AD?

2. What factors determine or initiate the dramatic decline in cognitive performances some years before AD diagnosis? Could a stroke (Snowdon et al., 1997) or a change in social environment (Fratiglioni et al., 2000) be precipitating factors?

Table 1.3. Different markers of subjects in preclinical AD phase

Markers

Significant references

Cognitive assessment Self and/or informant reports

(Discussed in this review)

Tierney et al., 1996; Schofield et al., 1997;

Non-cognitive symptoms Paraclinical examination Precipitating factors

Daly et al., 2000 Berger et al., 1999 Killiany et al., 2000

Snowdon et al., 1997; Fratiglioni et al., 2000

3. Is it possible to identify these subjects in the preclinical phase and to delineate a feasible preventive strategy?

To answer these questions further studies are needed. Specifically, the contribution of different markers of preclinical AD needs to be clarified and the information derived from different clinical aspects integrated (Table 1.3).

CONCLUSIONS

• Episodic memory deficits are dominant in both early clinical and preclinical phases of AD.

• These deficits in preclinical AD are generalizable across various dimensions of episodic memory.

• Preclinical episodic memory deficits may be seen several years (six to ten) before diagnosis, but the degree of impairment appears stable up until the period more closely preceding diagnosis.

• In addition to cognitive assessment, other markers such as family reports, depressive symptoms, and paraclinical examinations may help in identifying subjects in the preclinical phase of AD.

• Further studies are necessary to identify possible precipitating factors.

ACKNOWLEDGMENTS

This study was supported by the Swedish Council for Research in the Humanities and Social Sciences, the Swedish Council for Social Research, and the Swedish Medical Research Council.

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Address for correspondence: Laura Fratiglioni,

NEUROTEC, Karolinska Institute, The Kungsholmen Project, Aldrecentrum, Box 6401,

S 113 82 Stockholm, Sweden

Tel: +46 8 690 5818; fax: +46 8 690 5954; e-mail: [email protected]

Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics Edited by Khalid Iqbal, Sangram S. Sisodia and Bengt Winblad Copyright © 2001 John Wiley & Sons Ltd Print ISBN 0-471-52176-0 Online ISBN 0-470-84645-3

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