In this sample of subjects seen at ADCs, reverting from MCI back to normal or near-normal cognition a year later was fairly common: 16% reverted to < MCI, only slightly fewer than the 20% who progressed to dementia.
These results are similar to previously reported estimates of the rate of reversion in MCI. For example, in the Nun Study, 14.5% of subjects with MCI returned to normal cognition after 11 years of follow-up.3
Subjects more often stayed in their current cognitive state than transitioned to another, which was observed among the ADC subjects as well. Both studies may have underestimated the proportion of subjects returning to normal cognition, as clinicians are not blinded to previous patient diagnoses; clinicians may be disinclined to assign a diagnosis of normal cognition for a patient previously diagnosed as MCI.
Several characteristics were significantly associated with increased odds of improved cognition approximately 1 year later. These included nonamnestic MCI, especially single-domain; less severe MCI, as described by high MMSE score or low CDR sum-of-boxes score; not having an APOE ϵ4 allele; and the clinical attribution of MCI to a transitory condition, such as underlying medical illness or medication. Each of these characteristics (except attribution to a transitory condition) contributed significantly to a multivariable logistic model predicting reversion, suggesting that each factor is important in its own right. Unfortunately, the large amount of missing data on presumed etiology of MCI precluded more detailed analysis of the possible importance of that factor.
The survival analysis results from this study strongly suggested that patients who meet criteria for MCI and then improve remain at increased risk for retransitioning to MCI or dementia over the longer term. This finding held true even after controlling for several covariates associated with cognitive decline. One explanation may be that cognition often varies within individuals over time, so a patient who is just over the threshold to qualify as having MCI may later drop below that threshold if the timing of the next follow-up visit happens to fall during a period of relatively better cognition. Meanwhile, the underlying neurodegenerative process that accounted for the first episode of MCI may remain active and lead to long-term cognitive decline despite day-to-day fluctuations. Likewise, measurement error is inescapable in assessment of cognitive function and may also contribute to variation in classification of a patient's cognitive state over time.
This study had several strengths, including a large sample size, availability of many demographic and clinical characteristics from standardized assessments, and wide geographic scope; however, there were also some limitations. First, we were unable to distinguish reliably between normal cognition and “impaired, not MCI” at the follow-up visit, because of the inconsistent use of the latter category among the ADCs. As noted above, there was also a high frequency of missing data on the presumed MCI etiology at the first visit, as well as on APOE genotype. In addition, ADC subjects constitute a large multicenter case series, not a truly population-based sample; thus, the generalizability of results from ADC subjects to other clinical populations is unknown. Finally, we performed many tests of significance in this analysis, which increases the chance of a Type I error: falsely rejecting the null hypothesis that there is no association between the risk factor and the probability of reversion.
These findings contribute to a dilemma for clinicians who care for patients with MCI. As new treatments of the underlying neurodegenerative process are developed, it will be of critical importance to select candidates for trials who are most likely to be in the early stages of neurodegeneration. Patients with a high likelihood of reverting to normal or near-normal cognition on their own may reap little benefit from antidementia treatments while still being exposed to side effects, risks, and costs. Also, enrolling trial participants who are unlikely to have the targeted disease could affect the results of the trial in terms of both efficacy and risk. Conversely, patients who do revert to normal cognition may experience only a temporary remission of cognitive impairment.
To help resolve this dilemma, we hope that future research may be able to identify a subset of patients with MCI who are likely to recover and not relapse and who thus could be spared unnecessary antidementia treatments.