The primary finding of this study was that in healthy elderly subjects defined by normative psychometric performance and absence of significant functional decline by proxy report, longitudinal change in brain structure was associated with longitudinal change in cognition over a mean follow-up interval of almost 4 years. A decrease in hippocampus was associated with a lower memory score. A decrease in cortical gray matter and an increase in WMSH were both independently associated with lower executive scores.
The predictors of memory performance found in the present study are consistent with several cross-sectional studies of elderly patients and controls. Many investigators have described the relationship between hippocampal volume and memory performance in patients with mild cognitive impairment (Grundman et al., 2003
; Muller et al., 2005
; Saykin et al., 2006
) and dementia (Kramer et al., 2004
; Petersen et al., 2000
), and baseline hippocampal atrophy is reported to be a risk factor for subsequent decline (den Heijer et al., 2006
; Gluck, Myers, Nicolle, & Johnson, 2006
). Cross-sectional studies examining brain-behavior relationships in healthy elderly have been more mixed (Lye et al., 2004 Van Petten, 2004
; Walhovd et al., 2004
). The present study approaches the brain-behavior question with a longitudinal design. Our findings suggest that the relationship is fairly specific; hippocampus remained in the model predicting MEM, but cortical gray matter, WMSH, and lacunae did not. This lack of a significant contribution from WMSH and lacunae is similar to findings reported by Prins et al. (2005)
, who found that none of their markers of small vessel disease were related to decline in memory.
The relationships between executive functioning and brain structure appear more complex. We found that decreases in cortical gray matter and increases in WMSH were both associated with decline in EXEC. Cross-sectional and longitudinal studies have shown a relationship between cortical gray matter atrophy and EXEC decline in cognitive-impaired patients (Fein et al., 2000
; Mungas et al., 2001
). Van den Heuvel et al. (2006)
reported recently that an increase in periventricular WMSH volume paralleled a decline in mental processing speed in a nondemented, high-risk cerebrovascular group. Our findings add to the literature by demonstrating MRI predictors of EXEC in a longitudinal study of healthy elderly.
Whether specific cortical regions are differentially involved in EXEC cannot be addressed by the present study. Certainly, several studies have highlighted the importance of frontal regions for set shifting, inhibition, fluency, and other executive tasks (Demakis, 2004
; Goldstein, Obrzut, John, Ledakis, & Armstrong, 2004
; Mc-Donald, Delis, Norman, Tecoma, & Iragui, 2005
; McDonald, Delis, Norman, Tecoma, & Iragui-Madozi, 2005
), but anatomic specificity is far from established (Anderson, Damasio, Jones, & Tranel, 1991
; Collette et al., 2005
), and pathology in nonfrontal regions can affect frontal lobe activity (Tullberg et al., 2004
Our results are consistent with other longitudinal studies linking white matter disease with cognition in healthy subjects (Longstreth et al., 2005
; Schmidt et al., 2005
). Longstreth et al. (2005)
, for example, showed that subjects with worsening white matter grade experienced a greater decline on the Digit Symbol Substitution Test (Smith, 1973
) than did subjects with no change in white matter grade. The mechanisms underlying this effect are not clear but potentially include disruption of frontal-subcortical circuits (Cummings, 1998
; Owen, 2004
), cortical atrophy secondary to deinervation, or concomitant microvascular changes in the cortex.
We found that change in WMSH and not lacunae was related to EXEC. The opposite pattern was reported by Mungas et al. (2005)
, who found that WMSH was not associated with change in EXEC independent of cortical gray matter, lacunae, and hippocampus. One possible reason for the discrepant findings is that our study included only healthy controls, whereas Mungas et al. (2005)
included subjects with cognitive impairment and dementia, and these subjects showed greater range in lacunae. In the present study of healthy controls, there was a very restricted range of change in lacunae that likely limited our ability to identify relationships between lacunae and cognition. Our findings are more compatible with Longstreth et al. (2005)
, who reported that subjects with worsening white matter grade, compared with those without, experienced greater cognitive decline even after controlling for stroke between scans or occurrence of transient ischemic attacks. The relative impact of subcortical lacunae versus white matter lesions on cognition continues to be a subject of debate, and the fact that lacunae and white matter disease are strongly related makes determining their differential contributions to cognition change more difficult.
In our sample, MRI volumes showed greater age-related changes than did the cognitive and EXEC measures. The relationship between age and cognition in healthy elderly is somewhat controversial. Although group means on MEM and EXEC tests typically decline (Buckner, 2004
; Davis et al., 2003
; Wecker et al., 2005
), interpretation is confounded by increased variability and the fact that a large percentage of individuals demonstrate relative stability in cognitive scores over time (Cook et al., 2004
; Royall, Palmer, Chiodo, & Polk, 2005
). Our sample was a well-screened group of healthy elderly that for the most part appeared to remain healthy during the follow-up period. Despite this, changes on MRI were measurable, and these changes were still associated with changes in MEM and EXEC.
This study has several strengths. First, all subjects were carefully evaluated clinically both at baseline and follow-up to ensure that they were cognitively and functionally healthy. The assessments also included informant reports and consensus diagnoses at the study sites. These methods make it less likely that our findings were influenced by a few subjects with incipient neurodegenerative disease, although such a possibility cannot be entirely ruled out. Second, several MRI variables were considered simultaneously as predictors of cognitive change. The importance of considering multiple MRI variables is highlighted by Schmidt et al. (2005)
, who found that the association between changes in white matter lesion load and cognitive functioning were no longer significant when whole brain volume was added to the model. In our study, changes in both WMSH and cortical gray matter made significant contributions to declines in EXEC, implying that multiple brain components are relevant in understanding age-related cognitive change. These findings also emerged after carefully controlling for numerous other factors, including baseline cognitive performance, demographic variables, and baseline MRI measures. Third, all MRI variables were quantitative rather than semi-quantitative ratings. Fourth, our ability to discern brain-behavior relationships was likely enhanced by using psychometrically robust measures that were reliable and fairly normally distributed and did not have ceiling effects. This was particularly important given that cognitive changes in normal aging tend to be quite small and often not statistically significant (Cook et al., 2004
). The strong psychometric properties of our measures also enabled us to look separately at EXEC and MEM and determine that the neuroanatomical correlates of cognitive change were different for the two cognitive domains.
Age-related atrophy in the hippocampus and cerebral cortex are well documented, but the causes are not clear. It is not known to what degree atrophy can be attributable to normal aging or whether there are underlying neuropathological changes that reflect a disease state. One of the important implications of the current data is that at least for EXEC, one likely contributing factor to declining performance in healthy elderly is ischemic white matter disease. Accordingly, MRI markers of cerebrovascular disease should not be considered benign, even in a sample of healthy elderly, and reducing cerebrovascular risk factors such as high blood pressure, hypercholesteremia, diabetes, and smoking may be an important step toward optimizing cognitive stability.