This study provides evidence that an fMRI measure of hippocampal activation represents a quantitative imaging biomarker that predicts the degree to which individuals with MCI will demonstrate future cognitive decline, as well as the approximate rate of decline over the ensuing 6 years. Hippocampal activation is predictive of decline even after controlling for the degree of cognitive impairment at the time of scanning, age, education, gender, APOE status and hippocampal volume. As some individuals who declined were ultimately diagnosed clinically with probable AD, this finding suggests that relatively greater physiological activity of the hippocampal formation during memory task performance is present early in the course of prodromal AD, when symptoms are clinically detectable but mild enough that individuals are not considered to be demented.
Within this sample of MCI subjects, because relatively greater hippocampal activation precedes a relatively steeper slope of cognitive decline, we hypothesise that hippocampal hyperactivation may represent an attempted compensatory response to accumulating neurodegenerative pathology,10 20 22
such as synaptic dysfunction.9
Regardless of the mechanism, however, the observation that this physiological imaging biomarker predicts not only the likelihood of decline but also the relative degree and rate of decline suggests that it has utility for identifying individuals with MCI at highest risk of imminent cognitive decline, which would be valuable for a variety of types of studies, including clinical trials of putative disease modifying therapeutic agents.
The individuals with MCI in this study were volunteers from the community who participated in our longitudinal study of memory and aging. Based on a detailed clinical evaluation at the time of scanning, all of the individuals in this study were judged clinically to have been exhibiting mild symptoms of cognitive impairment in daily life, representing a change from their own previous baseline (CDR rating 0.5). Specific neuropsychological performance cut-off scores were not used to make this determination, but memory performance in this group, on the whole, was below the performance of participants in our sample who are considered clinically normal (CDR rating 0). In our cohort and other cohorts, mildly impaired groups defined on this basis are at greater risk of future cognitive decline than groups of normal individuals.11 16 33-35
As our approach to assessment enables a semi-quantitative (ordinal) grading of the degree of impairment within MCI,11
this can also be applied to grade the degree of worsening of cognitive symptoms over time. The use of change in CDR-SB as an outcome measure enables progression of cognitive symptoms to be graded, regardless of whether individuals “cross the threshold” to dementia. Recent data demonstrating that AD neuropathology correlates with subtle memory impairment in otherwise normal individuals has led some investigators to call for more widespread use of methods to grade subtle cognitive change rather than only conversion to a more impaired diagnostic category.36-38
In this study, hippocampal activation predicted the degree and rate of cognitive decline, even after controlling for other relevant measures (age, baseline degree of impairment, education, gender, APOE status and hippocampal volume).
The limitations of this study include the relatively small sample size and the specific characteristics of the participants that reduce generalisability. These individuals, along with a relative or close friend (informant), volunteer from the community for a memory study that involves annual assessments. As such, they may be more attuned than the average person to subtle changes in memory function in daily life. In addition, this sample is relatively well educated. Some of the findings in this sample may relate to education, cognitive reserve or similar factors, which we have not directly investigated.
As disease modifying therapies for AD enter clinical trials, it will be valuable to develop and test biomarkers that can identify non-demented individuals in whom AD neuropathology may be present (eg, with imaging tracers such as amyloid-positron emission tomography) along with biomarkers that can predict a high risk for imminent cognitive decline.39
Biomarkers that can predict which individuals are likely to experience the greatest degree or rate of cognitive decline may enable these individuals to be targeted more aggressively for clinical trials of agents to try to slow or prevent this disabling progression of symptoms.