Stages of the Illness

Figure 1 schematically illustrates a proposed time line for the development of AD pathology and its impact on functional status. It posits progressive degenerative changes and a "threshold" degree of neuropathological damage beyond which an individual manifests the clinical syndrome of dementia. By definition, that threshold is marked by observable decline in functional status that interferes with a person's activities of daily living. Ideally, decline is judged on the basis of changes from a particular person's premorbid status. In practice, it is often more crudely assessed by noting a disruption of common activities such as maintaining a checkbook, household responsibilities and chores, and personal hygiene. However, the more the determination of functional decline is adjusted for the patient's baseline, the less the clinical diagnosis will be affected by her socioeconomic, cultural, and educational background.

For heuristic purposes, the "journey" between normal brain functioning and clinical dementia can be divided into different stages:

1. Presymptomatic

2. Preclinical

3. Very early, "questionable" dementia

4. Mild dementia

5. Moderate dementia

6. Severe dementia

PRESYMPTOMATIC STAGE P RECH MIC Al STAGE CLINICAL DEMENTIA

PRESYMPTOMATIC STAGE P RECH MIC Al STAGE CLINICAL DEMENTIA

Fig. 1. Theoretical time line for Alzheimer's disease.

In the presymptomatic stage, there is an insidious pathological process in the brain, but there are no mental or behavioral symptoms, no impairment of everyday functioning, and no abnormalities on neuropsychological testing, even using tests sensitive to subtle decrements in performance. When baseline neuropsychological test data are available, results at the time of clinical evaluation would show no significant changes from the baseline. The existence of such a stage is supported by pathology series showing characteristic AD lesions in the absence of any observable or measurable clinical deficits on an antemortem evaluation (83-88,105-106). The notion of a presymptomatic stage is further bolstered by evidence of such a period in patients with Down syndrome who, in middle age, invariably develop a clinical dementia marked by AD pathology at autopsy (107-109). In this presymptomatic stage, some biological markers may be positive, permitting identification of candidates for intervention aimed at prevention of the disease.

In the preclinical stage, subtle deficits, especially in memory, are detectable by formal testing of cognitive performance. However, these deficits are not associated with any impairments in daily living. Such individuals would still rate a 0 classification on the CDR scale (87,97). Deficits in this stage can be detected by employing a comprehensive and sensitive battery of neuropsy-

chological tests (see Chapter 8 for a discussion of such batteries and preclinical AD).

As individuals approach the threshold for dementia, they may begin to exhibit subtle signs of functional and cognitive deterioration, suggestive of a clinical dementia. The Clinical Dementia Rating scale has designated this period with a score of 0.5. Such individuals exhibit mild forgetfulness, along with subtle impairment of judgment, home and community activities, or occupational functioning.* In one series by Morris and colleagues (87), all 10 of the individuals at this stage were found at autopsy to meet pathological criteria for AD. Several research groups have demonstrated that elders who exhibit this kind of mild impairment in memory and daily functioning go on to develop a full-blown syndrome of dementia at a rate of 10% to 15% per year, which is approximately 5 to 7 times higher than for age-matched individuals who do not exhibit such impairment (50,110).

By the time individuals reach a CDR stage of 1.0, there is no doubt that they have dementia, albeit of mild severity. Memory impairment interferes with everyday activities. There are growing difficulties handling complex problems and managing independence in household responsibilities and daily activities such as maintaining one's residence, handling finances, or reliably taking medication for concomitant medical illnesses.

Patients with dementia of moderate severity (CDR stage 2), exhibit significant memory loss, frequent disorientation, impairment of social judgment, and an increasing need for supervision in their daily living activities, including maintenance of personal hygiene and the cleanliness and safety of their residence. In the severe stages of the illness (CDR score of 3 and beyond), patients are totally dependent on others for personal care and everyday problem-solving. At the end of the disease, they lose the capacity to communicate, recognize caregivers, feed themselves, or walk without assistance.

According to this scheme for dementia staging, what is being "diagnosed" depends on whether we are considering the presypmptomatic or symptomatic stages of the illness. In the presymptomatic stages, what is being "diagnosed" is the underlying Alzheimer's pathological process, with the presumption that individuals with such markers are at high risk for developing a clinical dementia. In the symptomatic stages of the illness, what is being diagnosed is

♦Individuals in this stage of the illness are likely to need more time when interacting with health care professionals in order to understand and carry out instructions. Currently, the system often fails to identify such individuals or provide them with the additional time they require.

the clinical syndrome of dementia and a specific brain disease that accounts for it. Most often, current clinical practice focuses on the latter goal, as reviewed in Chapter 2. Often, the major effort is on excluding ("ruling out") other potential causes of dementia rather than making a positive diagnosis of AD. Most of the new diagnostic strategies reviewed in this book have focused, at least initially, on patients in the mild to moderate stages of the illness. In the past few years, there has been growing research (using longitudinal studies) on at-risk individuals in early or preclinical stages of the disease.

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