In this study we examined the relationship between cognition and everyday function both from a cross-sectional and longitudinal standpoint. In the cross-sectional analysis, we examined the relative associations between memory and executive dysfunction and the severity of functional impairment. The results suggest that memory and executive functioning are related to current functional impairment (with memory possibly having somewhat of a stronger relationship than executive functioning based on examination of p-values). In the longitudinal analysis we evaluated the association between baseline memory and executive function and future change, or decline in functional status. In this joint model only executive functioning was associated with a more rapid rate of decline. Thus, those individuals with greater executive dysfunction at baseline experienced a faster rate of IADL decline, whereas greater memory impairment at baseline was not independently associated with the rate of functional decline.
Why might memory function relate to contemporaneous everyday function but not to rate of future change in everyday function whereas executive function relates to both? There are at least two possible explanations. First, executive dysfunction may play a particularly important role in the progression of disability. For example, Royall (Royall, 2006
; Royall et al., 2004
, Royall et al.,2005
) argues for the central role of executive dysfunction in causing functional disability and in the conversion of MCI to dementia. Perhaps executive functions, because of their role in regulating and coordinating other mental functions, organizing behavior and generating responses, play a central role in a variety of everyday activities. Hence, when these functions begin to fail the person cannot function as well regardless of how well other cognitive functions are maintained. Further, because of the adaptive aspect of executive functions, intact executive function may permit successful compensation for failure in other cognitive domains, for example, memory. If so, failing executive abilities would then reduce compensatory ability and compound the loss of everyday function. Consistent with the present data, Royall and colleagues (Royall et al., 2005
) found that change in executive function, but not change in memory, was associated with change in functional impairment over time, also suggesting that executive dysfunction may be particularly important to longitudinal declines in everyday function.
A second possible explanation for the results of the current study is that executive dysfunction is simply a marker of greater cortical involvement. Thus, when executive functions fail other cortically-mediated functions begin to fail as well and when multiple cognitive functions fail, everyday function declines more rapidly. It is well known that AD affects the hippocampal formation early in the development of the disease (Braak & Braak 1991
; Hyman et al., 1984
), which explains the fact that memory is affected severely and this occurs early in the course of the disease. As the disease progresses other cognitive functions (e.g. executive functions among other domains) become increasingly affected (Welsh et al., 1992
). In this context, it is possible that once executive dysfunction is evident, AD pathology is affecting multiple neocortical areas (including, but not limited to the frontal lobes). Thus, executive functioning at baseline identifies how advanced the disease process is, and perhaps those with more advanced disease processes progress faster. In contrast, if memory alone is affected, functional decline may remain relatively unchanged or may not progress. Consistent with this idea is the fact that the lag between onset of amnestic MCI and conversion to dementia (if it occurs) is highly variable. During this time, which may extend over years, functional limitations are slight and distinct, and progressive loss of function is not seen. Evidence suggests that multi-domain MCI progresses to dementia more rapidly than amnestic or single-domain MCI (Alexopoulos et al., 2006
; Meyer et al., 2002
), which is also consistent with the hypothesis that cortical involvement carries a poor prognosis for everyday function. Arguing against the “more cortical involvement at baseline” hypothesis is the fact that we did not find that degree of cortical volume loss at baseline was predictive of faster functional decline. Ultimately to answer the question about whether there is truly something unique to executive dysfunction that is associated with a more rapid course of functional decline we will have to include measures not only of memory and executive functioning, but also of other cognitive domains (e.g., visuospatial functions). A strength of this study over most of the previous work was the use of psychometrically matched cognitive scales derived through item response theory methods, allowing for greater confidence that the pattern of associations found was not influenced by nonspecific measurement artifacts of the tests.
Unfortunately, additional analysis of subgroups of patients (e.g., those with MCI versus those with AD) was underpowered in the current study because of small sample sizes, and therefore such results were not presented. Preliminary, post-hoc analysis of our results indicated that in the MCI sample, there was a trend for baseline MEM to be associated with baseline IADL ratings but EXEC to be associated with longitudinal change in everyday function (very similar to the results that are presented using the entire sample). Interestingly MEM was primarily associated with baseline IADL ratings and change in IADL ratings in the AD group, suggesting that prominent memory dysfunction in this group may largely drive the progression of functional impairment. However, a better understanding of how the current results relate to specific subgroups of older adults awaits larger studies.
In addition to examining cognitive predictors of baseline and change in IADL ratings, we were also interested in examining neuroimaging predictors. In the final multivariate model we found that although hippocampal volume was associated with functional status in the cross-sectional analysis, baseline hippocampal volumes were not independently associated with rate of decline. That is, when the cognitive and neuroimaging measures were entered jointly as predictors, only executive functioning accounted for a significant proportion of variance in future daily function. Our results are consistent with the findings of Boyle and colleagues (Boyle et al., 2004
) who found that MRI measures of white matter disease did not improve the prediction of IADL performance in patients with vascular dementia over and above the contributions of cognitive variables. Both studies found that cognitive measures predicted daily function better than did brain imaging markers. Whether this is a generalizable finding, however, requires further study. For example, the research on the comparative value of imaging and cognitive predictors of conversion from MCI to dementia, a change defined in part by decreasing everyday function, is quite mixed (DeCarli et al., 2004
; Korf et al., 2004
; Visser et al., 1999
Although some previous studies (Boyle et al., 2004
; Farias et al., 2004
) have suggested that neuroimaging markers of CVD (e.g., WMH) relate to functional status, we did not find this relationship in the present study. In this study, WMH and lacunes were related to neither baseline functional status nor rate of change. The differences between studies may be partially related to differences in sample characteristics. The study by Boyle and colleagues (Boyle et al., 2004
) focused on individuals specifically selected because of CVD, and the study by Farias and colleagues (Farias et al., 2004
) examined a community-based group with low rates of dementia. Thus, the imaging predictors of rate of change may vary depending on the sample and in particular the distribution and severity of different brain pathologies within that sample. In the present case, both the distribution of clinical diagnoses and the results of neuropathology examinations in deceased patients from the parent sample (Reed et al., 2004
) suggest that the underlying pathology in this sample, while including a significant degree of CVD, is predominantly AD. For this reason it may be that neither lacunes nor WMH are particularly important markers of disease in this sample. Analyses of neuroimaging data from the parent study have shown that HV (and cortical gray matter) tend to be more strongly associated with cognition than WMH and volume of lacunes (Mungas et al., 2005
; Mungas et al., 2001
). It is therefore possible that the contribution of white matter disease in this sample with substantial AD is lesser.
A number of limitations deserve mention. How well our results may generalize to the aged population at large is unknown, but in this context the heterogeneity of this sample is strength. Community-based studies using autopsy confirmation of diagnosis have generally shown a substantial frequency of cases with “mixed dementia,” with reported rates ranging from 40% to 77% (Barker et al., 2002
; White et al., 2005
). Some degree of caution about the generaliz-ability of the results does seem warranted given differences between the study and parent samples. Although there were no differences in age, education, and global level of cognitive impairment (as measured by the MMSE) between the parent sample and current study sample, there were differences in some demographic variables (gender and race). Additionally, there was a higher drop out rate in the parent sample, although this did not appear to be a result of greater cognitive impairment in this larger group. There was no difference in diagnosis between those who dropped out and those who continued in the parent study, and the distribution of diagnoses was similar between the two groups at the baseline evaluation. The study sample likely contained a higher percentage of more frail or ill individuals, as evidenced by a higher mortality rate than the parent sample (38% vs
. 22%). Reasons for attrition in the study sample are not known; therefore it is possible that subjects may not have returned for additional assessments because they were either too impaired, or alternatively, because they were functioning sufficiently well that they were less interested in participating in the study. As such, the relationships reported here may be specific to the sample studied, and cross-validation would be necessary for determining the generalizability of the findings.
The current study focused on two cognitive domains, memory and executive function because prior studies had identified them as especially important to daily function. The measurement of other cognitive domains such as language and visuospatial abilities were not included. Thus the question as to whether executive functions play a special role in predicting functional decline or whether it is a marker of a more general effect of greater cortical involvement cannot be directly addressed by this study. If it is a more general effect we would expect that other measures of neocortical functions such as language and visuospatial skills may also be associated with rate of change. Using psychometrically matched instruments assessing a wider range of cognitive domains is an important direction for future research. A second issue is that the particular executive function scale used here was derived from working memory and verbal fluency tests and thus cannot be said to measure executive function in a comprehensive sense. Different measures of executive abilities might well yield different results. This is to an extent true of the memory composite as well, although the weighting of the memory measure—delayed verbal episodic memory—is at the core of a range of clinical memory tests and clearly represents a central aspect of memory function. The IADL rating scale, while widely used, is brief and non-comprehensive. Use of both informant- and performance-based instruments might permit more detailed and complex relationships between cognitive functions and everyday function to emerge. Additionally, although this study employed a broader range of MRI markers than previous studies, we nevertheless did not have a specific measure of frontal lobe volume or specific frontal white matter changes, which may be important for determining the contribution of this brain structure to the prediction of functional disability. Dysfunction of the prefrontal cortex may arise from direct neuronal loss, loss of input from neocortical association areas, and damage to frontal-striatal circuitry. Unfortunately, we are unable to identify the pathway or the etiology of this dysfunction in this study, and future studies with more specific MRI volumetric measures of frontal lobe volume are needed. Additionally, the reliability of identifying lacunes is known to be problematic. In this study one rater (a board certified neurologist) identified lacunes on MRI scans for all participants. Further evaluation of this approach is needed.
In summary, previous studies have shown that individuals with greater global cognitive dysfunction at baseline experience a more rapid rate of decline in IADLs than individuals with milder impairment overall (Feldman et al., 2001
; Schmeidler et al., 1998
). The current results extend these findings to show that in particular, those patients with a greater degree of executive dysfunction at initial assessment tend to experience a more rapid decline in ratings of their functional status over time. Although more atrophic hippocampi at baseline were associated with a faster rate of decline in everyday function, this was not independent of the effects of executive dysfunction. Thus, whereas these data suggest that executive abilities may play a particularly important role in predicting decline of everyday function, various issues leave that an open question. However, these observations provide strong support for the value of exploring the effects of specific domains of cognitive impairment on daily function and demonstrate that the factors predicting current status may differ from those that predict change. Understanding the difference may refine our understandings of how brain pathology is eventually expressed in disability.