Relatively few neuropathology studies have been completed on participants during the MCI stage of the illness. Some investigators contend that this stage of MCI is, in fact, AD but also indicate that these participants may be more clinically advanced than others in the literature.51, 52
The Religious Orders Study has followed up a group of nuns and priests for many years and has an excellent autopsy rate. In general, they have found that approximately 60% of the participants with MCI have neuropathological evidence of AD, but indicate that vascular disease also accounts for a significant degree of the neuropathological features.53
Other studies have highlighted the importance of neurofibrillary tangle density in accounting for the symptoms of MCI.54
Two studies from the Mayo Clinic published in the Archives of Neurology
shed additional light on these participants.55, 56
One study evaluated participants who died while their clinical classification was MCI and found that most had a low probability of having the neuropathological features of AD at that point in time.55
However, it appeared as if the participants were in transition to greater degrees of pathological involvement. A second study observed participants who had been previously diagnosed with MCI and progressed to dementia and characterized these participants as having the ultimate pathological characteristics.56
This study indicated that, while most of the participants with aMCI developed AD, a considerable proportion, 20% to 30%, developed another type of dementing disorder, indicating that, while the clinical criteria for aMCI likely predict AD, they are not absolutely specific.
In the past 10 years, there have been numerous clinical trials on aMCI, testing most of the current therapies available for AD.29, 57, 58
All of the acetylcholinesterase inhibitors have been evaluated, and with one partial exception, results of all these analyses were negative ().29, 57–60
These trials, cumulatively, have involved between 4,000 and 5,000 participants. One trial with rivastigmine, two with galantamine, and one with rofecoxib failed to achieve the anticipated rates of progression from MCI to AD and, consequently, had to be extended, resulting in a lack of power.57–59
The rivastigmine trial was conducted in multiple countries with multiple languages and likely recruited a heterogeneous group of participants with very mild disease.57
Hence, the rate of progression was lower.
Two trials involving galantamine used mild entry criteria and required a more advanced degree of “conversion” of CDR 1 rather than the clinical diagnosis of AD as an end point.59
Hence, this criterion may have inadvertently required participants to remain in the MCI stage for a longer period, resulting in a lower rate of progression than anticipated. However, this trial almost achieved its anticipated rate and had a suggestion of a therapeutic response.59
The rofecoxib trial initially required a more stringent degree of memory impairment and had to loosen the inclusion criteria to recruit enough participants. This may have contributed to its low rate of progression, necessitating an extension of the trial.58
Consequently, for a variety of reasons, all of these trials did not meet their anticipated therapeutic goals.
The Alzheimer’s Disease Cooperative Study conducted a therapeutic trial on participants with aMCI to test high-dose vitamin E and donepezil and achieved its anticipated progression rate of 16% per year.29
It is interesting to note that virtually the same recruitment techniques were used in the ADNI, and this study has achieved a virtually identical progression rate of 16% per year.11
The Alzheimer Disease Coopertive Study suggested a therapeutic effect of donepezil for the first 12 months in all participants with MCI and up to 24 months for the Apolipoprotein E ε4 carriers. However, because the study was designed to assess effects over 36 months, the ultimate outcome was negative.29
A subsequent 48-week trial of donepezil alone failed to replicate the Alzheimer Disease Cooperative Study results, and, hence, no treatments have been approved for MCI.60
From a clinical trials perspective, if one were designing a disease-modifying therapeutic trial involving participants at the MCI stage, one could consider aMCI criteria of a degenerative pathogenesis and require positive imaging and biomarker data to enrich the clinical population to enhance the likelihood of progression to clinical AD. This could very well be consistent with the presumed therapeutic target of the agent. That is, if one were testing an amyloid-specific agent, one could use aMCI clinical criteria and stratify participants according to their apolipoprotein E ε4 carrier status, amyloid imaging, or markers of CSF involving amyloid to create a subset of participants who are more likely to progress rapidly and harbor the underlying amyloid pathological substrate.
While the construct of MCI has engendered a great deal of attention (), it has also raised a great deal of controversy. Much of the concern about the construct pertains to its heterogeneity, lack of specific ability to predict outcome, and vagueness of the criteria, e.g., the degree of cognitive impairment in non-memory cognitive domains and the degree of functional impairment. depicts many of the sources of variability in studies on MCI. A few deserve mention.
Sources of Variability in MCI Studies
The source of participants is a prominent aspect of variability in many of these studies. As mentioned earlier, participants from a referral clinic, memory disorders clinic, or an AD center likely have a higher prior probability of having AD at the outset. On the contrary, participants who are recruited proactively through an epidemiological procedure are likely more heterogeneous and have multiple medical comorbidities and are “less pure” from an AD substrate perspective. These participants would cause more “noise” in the system if used in clinical trials but likely represent the reality of MCI in the population.
Several early studies retrospectively applied MCI criteria to previously collected data sets.16
This approach necessitates the use of an algorithmic model to retrofit previously acquired neuropsychological data.
An issue inherent in the discussion of neuropsychological test scores pertains to the use of normative data on neuropsychological instruments and cutoff scores. It is important to emphasize that MCI is not just a neuropsychological entity. Although findings from neuropsychological testing constitute a cornerstone of the objective assessment, the ultimate diagnosis involves more than just a set of cognitive test scores.
Two other sources of variability merit discussion. In longitudinal studies, the blinding of the investigators to the previous clinical diagnoses is important. That is, if the investigators know that the participants were previously classified as having MCI, they would be less likely to label them as being cognitively normal on a subsequent visit. This is not necessarily inappropriate since it may reflect the natural variability of the clinical course of these participants and may actually consider this in the diagnostic process. However, in a research setting, it can confound the interpretation of the data. Hence, many studies render the clinical investigators blind to previous clinical classifications. These types of studies lead to higher degrees of “reversion” to normal.
Finally, we need to address the issues of MCI as a clinical or pathological entity and the constructs of sensitivity and specificity. That is, when we make the diagnosis of MCI, does this refer to the clinical state of the patient or the underlying pathophysiological features, leading to the symptoms, or both? It might be most productive to keep these entities separate.
These studies, coupled with the neuropathological findings, suggest that the clinical criteria for aMCI may designate a mildly impaired set of participants, many of whom, but not all, have the underlying neuropathological features of AD. This has implications for the labeling of the clinical condition of MCI and the design of future trials. It may be inappropriate to label participants at the aMCI stages as having AD, or even incipient or prodromal AD because many will not eventually evolve to AD, and hence, we cannot afford to mislabel all participants with MCI as having AD features because this is the only label that they will perceive. In other words, participants and families will only “hear” the AD part of the label, yet we will be incorrectly labeling some of them because not all will progress to AD. Therefore, it might be preferable to use an etiologically neutral term such as “MCI,” couple that with a suspected pathogenesis through history and ancillary testing, and explain to the participants the possibility that this term may imply development of AD in the future or it might imply stability or, even less commonly, improvement in their clinical symptoms. This approach may be more consistent with the longitudinal data.
In 2001, the American Academy of Neurology published an evidence-based medicine practice parameter on MCI and recommended that physicians should identify and monitor patients with MCI, because these persons had an increased risk of developing dementia.61
At that time this recommendation was based on relatively few longitudinal studies. Now, the literature has expanded greatly, and numerous prospectively designed longitudinal studies are available from which to draw conclusions. As such, the American Academy of Neurology is repeating the practice parameter exercise at present reassessing the clinical utility of MCI. In addition, to assess the clinical acceptance of the construct, a recent survey by the American Academy of Neurology indicated that 80% of neurologists use the term “MCI” and find it useful at describing this type of patient, implying that the construct of MCI is becoming clinically useful and gaining more widespread acceptance.62
In conclusion, the construct of MCI has influenced the field of aging and dementia in several significant spheres. It has served to focus the attention of investigators on the earlier, prodromal states of many cognitive disorders. Research programs ranging from epidemiological studies to explorations of the mechanisms of disease have been influenced by the construct of MCI, and, hopefully, these investigations will lead to more effective therapies. This work has stimulated discussions concerning new clinical criteria for conditions such as AD and will likely have an effect on the development of international classification systems for cognitive disorders.63
Ultimately, we hope that this work will lead to the development of imaging and biomarkers for the asymptomatic stages of neurodegenerative diseases. That is, by augmenting our knowledge of the role of imaging and measures in the MCI stage, we will be able to validate their utility in predicting the progression to more advanced stages of the disorders and, hence, suggest their further utility by being applied to the asymptomatic stages of the conditions. As such, MCI will have served an important role in advancing our understanding of disease mechanisms with the ultimate goal of finding preventive therapies.