DENVER—Neurologists are very good at diagnosing Alzheimer’s disease. Their clinical impressions have been shown to match autopsy findings in 80% to 90% of suspected Alzheimer’s disease cases, observed Ronald C. Petersen, MD, PhD, Director of the Alzheimer’s Disease Research Center at the Mayo Clinic in Rochester, Minnesota.

Mild cognitive impairment is much harder to spot, though, because it is so subtle that it can be, and often is, mistaken for normal aging. In fact, recent research has shown that mild cognitive impairment very often progresses to Alzheimer’s disease, so clinicians who detect it may effectively be finding Alzheimer’s disease at a much earlier stage.

That provides an opportunity for very early intervention and planning for the patient’s future while the patient can still participate, said John C. Morris, MD, Co-Director of the Alzheimer’s Disease Research Center at the Washington University School of Medicine in St. Louis. Drs. Petersen and Morris discussed issues related to mild cognitive impairment at the 54th Annual Meeting of the American Academy of Neurology (AAN).

MORE NORMAL THAN NOT

Other cognitive domains—attention, language, visuospatial skills, and executive function—and activities of daily living are usually unaffected in mild cognitive impairment. “These people look more normal than not, but there is a slight inconvenience caused by the memory impairment,” Dr. Petersen said.

IS IT AGE OR IS IT DEMENTIA?

Mini Mental State Exam (MMSE). In the literature, mild cognitive impairment is associated with an MMSE score of greater than 24 out of 30, which Dr. Petersen described as “ ‘normalish’ but not quite as good as normal controls.” While a typical MMSE score in mild cognitive impairment is in the range of 26 to 28, he stated that the MMSE exam has recently been found to be relatively insensitive in the early stages of cognitive impairment.

Full-Scale Intelligence Quotient (IQ). The average patient with mild cognitive impairment has a full-scale IQ of 97 or 98 versus about 100 for normal controls. This difference is statistically significant but is not likely to be clinically significant.

Clinical Dementia Rating (CDR). A CDR of 0 signifies no dementia while ratings of 1 through 3 correspond with mild, moderate, and severe dementia, respectively. A 0.5 rating is assigned for the questionable dementia that characterizes mild cognitive impairment but may also be present in mild probable Alzheimer’s disease.

Global Deterioration Scale (GDS). The GDS rates a variety of domains (such as memory, orientation, hobbies, participation in the community, and personal hygiene) on a 1-to-7 scale from “normal” to “severely impaired.” The rating, or summary score, is typically between 2 and 3 in mild cognitive impairment.

DIAGNOSTIC TOOLS, DISEASE PROGRESSION

On magnetic resonance imaging, their brains may show a small degree of generalized atrophy and specific atrophy of the hippocampus. These findings are not diagnostic, but they do give the impression that the neuropathologic underpinnings of incipient Alzheimer’s disease are present and that mild cognitive impairment is manifest, Dr. Petersen said.

Long-term follow-up of patients with mild cognitive impairment supports that conclusion. About 12% of these patients progress to probable Alzheimer’s disease annually versus only 1% to 2% of normal controls. Although roughly 80% of mild cognitive impairment cases progress to Alzheimer’s disease within about six years, that does not occur in all cases. That is because some patients with mild cognitive impairment actually have other conditions that are clinically similar to Alzheimer’s disease, such as hippocampal sclerosis.

AGE-RELATED COGNITIVE DECLINE—AN EXAGGERATED ASSUMPTION?

He based those statements on longitudinal data for 82 healthy adults collected during a 15-year period starting when the subjects were in their mid-70s. Many of these subjects did not develop any dementia over the study period and performed as well on psychometric tests when they were approaching age 90 as they did 15 years earlier, reported Dr. Morris. Those subjects who did develop dementia also had stable cognitive performance up until the point where clinical evidence of dementia was recognized by an experienced physician who generally relied on the observations of the subject’s spouse or other close relative or friend that there had been a decline in the individual’s ability to carry out his or her usual activities. For those fortunate enough to escape dementing illness, however, the data illustrate that cognition can remain quite stable with advancing age, said Dr. Morris. “We need to know what is normal before we can detect impairments, and I am trying to set a pretty high bar for normal,” he noted.

A CLINICAL DIAGNOSIS

Although cognitive test results are useful in the evaluation, the observations of those closest to the patient with suspected mild cognitive impairment—not patient self-reports—are the most sensitive predictors of cognitive change, asserted Dr. Morris. “Sometimes people who complain the most bitterly about their memory are the ones who remain nondemented,” he remarked. Separate interviews are a reliable method of obtaining information from those who know the patient best. Clinicians should ask about any change in memory, problem-solving ability, and the ability to handle tasks that the patient used to be able to perform.

One can be reasonably certain that the patient has very early stage Alzheimer’s disease even if the clinical evaluation only suggests questionable dementia. After completing long-term follow-up on a large cohort with a CDR of 0.5, Dr. Morris found that dementia progressed to a CDR of 1 or greater within eight years in all cases. Furthermore, autopsy confirmed a dementing illness in all of those who died during follow-up. The illness was almost always Alzheimer’s disease, although a few patients had an Alzheimer’s disease and vascular dementia combination or frontal temporal dementia.

CHOLINESTERASE INHIBITOR THERAPY FOR MILD COGNITIVE IMPAIRMENT

Cholinesterase inhibitors are effective, although they are currently approved only for mild to moderate Alzheimer’s disease and not for mild cognitive impairment. Clinical trials are under way to evaluate their effectiveness in mild cognitive impairment, however.

Some neurologists are already convinced that cholinesterase inhibitors are appropriate for mild cognitive impairment, though, because of mild cognitive impairment’s close relationship to Alzheimer’s disease and the response of Alzheimer’s disease to these drugs in earlier clinical studies.

Emerging data from previous trials of other cholinesterase inhibitors suggest that initiating therapy early in the course of Alzheimer’s disease maintains function at a higher level, at least temporarily, than if the drugs are initiated when the disease is more advanced. Such data support the rationale for starting treatment even in patients with mild cognitive impairment, although definitive studies of the effectiveness if cholinesterase inhibitors in mild cognitive impairment have yet to be reported.

NR

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