In many ways, the frustration experienced by
patients struggling with mild cognitive impairment
(MCI) is matched by the frustration of
clinicians facing the challenge of managing this
heterogeneous condition. The prognosis can be
variable, and no proven therapies exist.
Would it be less frustrating if a diagnosis of MCI could definitively identify patients who would eventually progress to Alzheimer disease (AD) or another form of dementia? What if identifying those patients would allow for early therapeutic intervention that would delay or prevent that progression? In reality, although dementia does ultimately develop in the majority of patients with MCI, little is known about how quickly MCI progresses to dementia. Some population-based studies suggest that as many as 44% of patients who meet diagnostic criteria for MCI will no longer meet those criteria on follow-up examination.1 To date, no therapies are approved specifically for use in patients with MCI, and the few clinical trials that have included patients with MCI have yielded little more than promising trends.2-11
In practice, these clinical unknowns must be balanced against the very real possibility that MCI will progress to dementia. This necessitates an approach to patient care that is both delicate and diplomatic.
"You obviously want to be cautious about what you tell patients. You don't want to give them the impression that, for certain, they're going to get Alzheimer disease," said Allan I. Levey, MD, PhD, professor and chair of neurology at Emory University in Atlanta, and director of the Emory Alzheimer's Disease Research Center. "But it's also important to educate the patient about what MCI is and that it does carry a risk; that's the reality. People want to know what they can do, so it's our job to try to answer that question directly."
With so much ambiguity already surrounding MCI, ensuring an accurate diagnosis is essential. Although experts have preferences for different neuropsychological tests, most advocate a battery of tests that can distinguish MCI from normal age-related deficits of cognitive impairment and that can distinguish MCI from dementia by verifying that any influence on activities of daily living has not affected the patient's functional independence. All emphasize that because MCI is usually diagnosed in patients with whom the physician has no previous relationship, a thorough patient history—obtained from both the patient and his or her caregivers—can be as important as test results for making the diagnosis.
"Ideally, you're most sure of the diagnosis when not just the patient is aware of the problem, but another person also confirms that a problem exists, that it is new, and that it is getting progressively worse," said Martin R. Farlow, MD, professor of neurology at Indiana University School of Medicine in Indianapolis, and associate director of the Indiana Alzheimer Disease Center.
A relatively new development in the study and management of MCI is the concept of narrowing the diagnosis to 1 of 4 subtypes: amnestic or nonamnestic, and affecting 1 or multiple cognitive domains. Before a 2003 international conference in Stockholm at which the narrower subtypes were outlined,12,13 discussion of MCI was largely focused on memory impairment and the amnestic subtype.
The amnestic subtype is considered to be the potential precursor to AD, with conversion rates estimated at 10% to 15% per year. Although it was initially thought that amnestic MCI would progress to AD and nonamnestic MCI would progress to other forms of dementia, more recent research14,15 suggests that there is quite a bit of crossover between the subtypes and their outcomes, further complicating the clinical picture.
"The [documented] conversion rates are most clear for the amnestic subtype. So in my practice, if someone meets those criteria, I'm able to give them pretty reliable information about conversion rates—that there is an approximately 50% chance of conversion to AD within 5 years," Levey said. "If the patient is not amnestic, it encourages me to look for other causes of cognitive deficits."
Those other causes can include underlying cerebrovascular disease, sleep apnea or other sleep disorders, and behavioral issues, such as depression—conditions that, perhaps ironically, may be managed more successfully than amnestic disorders. To assist in the differential diagnosis, some clinicians advocate performing an MRI scan on any patient with suspected MCI. Research also suggests that different patterns of medial temporal lobe atrophy on MRI can differentiate MCI subtypes16 and can predict progression, particularly to AD.17-19
"In my practice I get an MRI on anyone with objective memory loss," said Ranjan Duara, MD, medical director of the Wien Center for Alzheimer's Disease and Memory Disorders at Mount Sinai Medical Center in Miami Beach, Florida, and associate professor of medicine at the University of Miami. "If the MRI clarifies that the person doesn't have an underlying neurological condition, then that can be helpful in identifying other factors. You might find out that there are psychiatric or medical issues, or use of medications or alcohol that you didn't know about."
SUBGROUPS AND SECONDARY END POINTS
Unfortunately, even with an accurate diagnosis, the therapeutic options for MCI are limited. Few drugs approved by the FDA for mild to moderate AD have been studied in patients with MCI. Although the acetylcholinesterase inhibitor donepezil (Aricept) was associated with delayed conversion to AD in the first 12 months of the 2005 Memory Impairment Study,2 the statistically significant between-group difference in conversion rate had dissolved by the end of the 3-year study.
Researchers, nonetheless, have been encouraged by the results of the study, not only because of the early success in the entire group treated with donepezil, but also because the results showed even stronger evidence of the drug's effectiveness in carriers of apolipoprotein (APOE) e4 alleles, which have been associated with more rapid progression from amnestic MCI to AD.20
Of the 769 patients with amnestic MCI in the study, possible or probable AD developed after 12 months in only 16 of the 253 patients who received donepezil (5 mg/d, increased to 10 mg/d after 6 weeks), compared with 33 of the 257 patients who received vitamin E (1000 IU daily, increased to 2000 IU daily after 6 weeks) and 38 of the 259 patients who received placebo. Although the conversion rates for the 3 treatment groups were not significantly different at 3 years, when researchers looked specifically at patients who tested positive for the APOE e4 allele, the conversion rate in the donepezil group was significantly lower than in the placebo group for the entire study period.
An MRI analysis of a 131- patient subset of that study population, published in 2007, found that treatment had no effect on annual percent-volume change in the hippocampus, entorhinal cortex, whole brain, and ventricle; however, the researchers did report a non-significant trend suggesting reduced hippocampal atrophy in APOE e4 allele carriers treated with donepezil.3
An earlier, smaller-scale trial of donepezil also failed to demonstrate efficacy in its primary end points and improvement on the New York University (NYU) Paragraph Recall Test and the Clinical Global Impression of Change scale in the intent-to-treat population.4 In that 24-week trial, the 133 patients with amnestic MCI who were randomly selected to receive donepezil (5 mg/d for 42 days, increased to 10 mg/d) were significantly more likely to demonstrate improvement on the cognitive subscale of the AD Assessment Scale than were the 137 patients who received placebo.
Other drugs that are FDA- approved for mild to moderate AD have fared less well in clinical trials of the MCI population. The most recent trial to be published, the Investigation into the Delay to Diagnosis of AD with Exelon (InDDEx) study,5 found no significant benefit of the cholinesterase inhibitor rivastigmine (Exelon) on the time to clinical diagnosis of AD in more than 1000 patients with MCI. During the 48-month study, AD was diagnosed in 17.3% of patients who were randomly selected to receive rivastigmine (0.5 mg bid, gradually increased to a maximum of 12 mg/d) and in 21.4% of those who received placebo.
Researchers also found no significant between-group differences regarding change from baseline in performance on neuropsychological tests. Interestingly, treatment benefits were not seen even in a subpopulation of APOE e4 allele carriers. However, the authors noted that their inclusion criteria from the NYU Delayed Paragraph Recall Test were not adjusted for age and education. By contrast, delayed recall inclusion criteria for the Memory Impairment Study were adjusted for education level.
Two earlier studies of the cholinesterase inhibitor galantamine (Razadyne),6,7 which is also FDA-approved for mild to moderate AD, found no statistically significant benefits at 24 months in improving cognition or delaying conversion to AD in an MCI population of more than 1000 patients. Some statistically significant treatment-related differences were seen in population subgroups based on NYU delayed or immediate recall test performance.
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