Overall, dMCI patients who worsened on the CDR-SB after 2 years had more atrophy in the bilateral insula and left lateral temporal lobe on baseline MRI when compared to the stable dMCI patients. There was also a trend for smaller baseline precuneus volume in the dMCI patients who declined. The decliners were also older, had lower baseline performance on category fluency and a visuospatial task, and reported fewer dysexecutive symptoms than their study partner when compared with stable dMCI patients. With the exception of hypertension that was more prevalent in the decliners, no other cardiovascular or health risk factors differed between the groups. These results suggest that dMCI patients who decline clinically over 2 years may have unique brain MRI and clinical features.
The finding that the overall distribution of baseline MRI volumetric differences was more posterior than anterior in the dMCI patients who declined was somewhat unexpected. A previous study comparing controls and dMCI patients found more atrophy in the left prefrontal cortex [7
]. However, atrophy in the lateral temporal lobe and insula in dMCI patients who decline may provide hints about the clinical trajectory. For example, patients with dementia with Lewy bodies can have volume loss in bilateral temporal lobes, frontal lobes and insula when compared to controls [29
]. Medial temporal lobe atrophy may be highly predictive of AD [31
], but atrophy in other posterior regions may be less specific for AD. Several studies using VBM suggest that amnestic MCI patients who convert to AD have atrophy in the precuneus, posterior cingulate and temporoparietal areas [32
After controlling for age, the dMCI patients who declined over 2 years had lower baseline scores on tests of category fluency and spatial location with a trend for lower scores on visual memory. All MCI patients in this study met criteria for dMCI at baseline and did not have clinical features of amnestic MCI. Interestingly, the decliners did not have significantly lower baseline scores on executive function when compared to the stable dMCI patients, supported by the fact that both groups had a similar degree of executive dysfunction at baseline. The groups were also comparable on global measures of cognition (MMSE) and IADLs (FAQ), providing further support that the decliners were not more impaired than the stable dMCI patients at baseline. Low score on category fluency is a commonly studied predictor of AD [35
], and low scores on visuospatial tasks can be associated with other neurodegenerative diseases, such as dementia with Lewy bodies, corticobasal degeneration, and frontotemporal dementia [37
]. Thus, the dMCI patients with lower scores on tests of visuospatial skills are likely to progress clinically and may have an underlying neurodegenerative disease.
Although there were no differences in the number of informant-rated dysexecutive symptoms (DEX-informant), the dMCI patients who progressed clinically reported fewer dysexecutive symptoms than their informants (DEX-difference score), when compared with stable dMCI patients. Decreased awareness of cognitive symptoms (e.g. anosognosia) has been reported in individuals with MCI and has been linked to midline cortical structures [41
] and frontal cortex [42
]. It is possible that a discrepancy between informant and patient reports is a more sensitive predictor of clinical progression than the absolute number of dysexecutive symptoms.
Over 2 years, 2 of the stable dMCI patients reverted to normal. Indeed, some of the participants in the stable group may remain healthy and not have a neurodegenerative disease. Several studies found that approximately 25% of non-amnestic MCI patients revert to normal [5
]. It is also possible that dMCI patients who remain stable over the first 2 years may have a longer disease course. A recent meta-analysis [43
] found that the annual conversion rate to dementia for non-amnestic MCI patients was 4.1%, whereas the annual conversion rate for amnestic MCI was 11.7%. It is also important to keep in mind that the mean age of the dMCI patients in this study was 64 years of age, which is younger than reported in most studies of MCI and may also affect progression rates. Isolated executive dysfunction can be a prodromal stage for several neurodegenerative diseases, including AD, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, vascular dementia, frontotemporal dementia, and Parkinson disease [44
]. Whitwell et al. [45
] found MRI atrophy in the basal forebrain and hypothalamus in 9 dMCI patients compared to controls. Three of these dMCI patients converted to dementia with Lewy bodies, and another 3 to AD. We previously reported AD neuropathology with an atypical distribution in a non-demented participant with isolated executive dysfunction [46
]. Recent studies link executive dysfunction with cardiovascular disease and prodromal vascular dementia [47
]. However, the dMCI patients with evidence of significant vascular disease on brain MRI were excluded from our study, and the 2 dMCI groups only differ on the prevalence of hypertension but not other cardiovascular and medical risk factors.
The current study has several limitations. First, the sample size is relatively small, and the null finding for differences in the majority of the baseline neuropsychological tests may be an underestimate. However, a focus on non-amnestic MCI is relatively recent, and larger sample sizes are currently being recruited. Longitudinal studies are currently needed to determine the diagnostic outcome of the dMCI patients. Comparisons with other MCI subgroups would also be useful.