The main finding in the present study is that in healthy adults, age-sensitive cognitive skills are differentially associated with regional white matter integrity. Whereas, in accord with previous reports, diffusion-based indices of white matter microstructure evidence broad age-related declines, their relation to cognitive performance (summarized in ) is quite complex.
Not surprisingly, one region-one task dissociations are rarely if ever observed. The ROIs in which white matter microstructure was measured in this study involve multiple neural circuits, and the tasks employed in this investigation rely on multiple cognitive processes. Nonetheless, the pattern of results can be interpreted in light of previous findings and theoretical expectations outlined in the introduction. Reduced integrity of the anterior cerebral regions that included prefrontal white matter and the callosal fibers that connect the anterior segments of the two hemispheres, along with parietal association white matter was associated with reduced speed of processing, a hallmark of cognitive aging (Birren, 1963
; Salthouse, 1985
). Processing speed was unrelated to integrity in the middle part of the brain. In contrast, all indices of episodic memory exhibited significant associations with the white matter anisotropy in the temporal and medial temporal regions. Executive functions that require at least some memory support, i.e., working memory span or capacity, also showed significant links to the middle cerebral white matter integrity. Notably, other executive functions that require little memory support but are focused on response selection and inhibition as well as management of conflicting task demands showed no temporal lobe involvement and evidenced significant correlations with the integrity of posterior brain regions.
Several more subtle dissociations were also observed. For instance, verbal processing speed depended on local anterior white matter integrity, whereas nonverbal processing speed depended on a fronto-parietal network (i.e., the superior longitudinal fasciculus or superior fronto-occipital fasciculus). Contrary to our hypothesis, speed-of-processing indices were not associated with global white matter deterioration but appeared to be linked to regional differences in microstructure that were similar to the putative substrates of executive functions (i.e., frontal-parietal association areas). Such specific association argues against the view of speed of processing as the index of generalized aging.
The literature on white matter substrates of age differences in processing speed is inconsistent. In older adults, reaction time measured on simple tasks is related to global indices of white matter integrity in some (Deary et al., 2006
) but not other (Grieve et al., 2007
; Charlton et al 2006
; 2007) samples. On the other hand, links between regional anisotropy and visual detection speed (Madden et al., 2004
) as well as the magnitude of speed influence on episodic retrieval (Bucur et al., 2007) have been reported. In the past, we have found a significant association between prefrontal (but not posterior) gray matter volume and speed of processing on a series of mental imagery tasks (Raz et al., 1999
). Taken together, the results of these studies indicate that quick cognitive processing depends on the integrity of at least the prefrontal and anterior callosum fibers, and, as suggested by our present findings, also the fronto-parietal fibers, i.e. the networks that are considered the neural substrate of executive controlled processes. In classic theories of disconnection syndromes, a breakdown of transmission in the white matter connective fiber bundles disrupts or slows the mode of cognition that relies on the joined regions (see Catani & ffytche, 2005
). Thus, our results support the idea that this slowing stems from degraded neural transmission along the axons of the aging brain.
We found age-related reductions in a widely distributed network of white matter connections to be associated with declines in working memory. These networks ranged from anterior (prefrontal, anterior callosum and internal capsule) to posterior (posterior internal capsule, temporal and occipital white matter) reflecting the importance of intact white matter across the brain for working memory performance. Such distributed support of working memory with age has been demonstrated previously with coarser regional measures (Charlton et al., 2006
, 2007; Deary et al., 2006
; Raz et al., 2007
). The current finding bolsters the understanding that working memory, as assessed by the span and n
-back tasks, is a multidimensional construct that reflects the state of a wide range of neural substrates encompassing most of the deep cerebral white matter.
The current finding of the association between reduced anisotropy of the posterior white matter (parietal, splenium, and occipital) and higher Stroop interference cost likely reflects the influence of distributed white matter systems such as the superior fronto-occipital fasciculus, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus, which also have projections anterior to the prefrontal cortex. Age-related reduction in fiber integrity in these areas can have far-reaching effects in the brain. These results are also consistent with the literature on top-down modulation of posterior brain regions during inhibition and attention tasks (e.g., Erickson et al., 2008
; Hopfinger et al, 2000
) and with the notion that age-related alterations in top-down modulation or its substrates can influence multiple cognitive domains (Gazzaley & D’Esposito, 2007
). A fiber-tracking study by Sullivan and her colleagues (2006)
found that while regional segments of corpus callosal fiber properties did not predict Stroop interferences scores per se
, they did predict word reading after controlling for age, predominantly in the posterior segment fibers in a sample of 10 older adults. The current findings are in accord with their posterior callosum findings and expand the regions reported in the literature to include the parietal and occipital white matter.
We observed an association between the costs of task switching and the integrity of a fronto-parietal network of white matter regions. Specifically, age-related reductions in prefrontal, anterior corpus callosum, superior/posterior parietal, and occipital white matter integrity were linked to higher switch costs. These results are consistent with functional studies that found that prefrontal and parietal activations support a diverse set of switching tasks (Wager et al., 2004
) and a recent DTI and fMRI study found that decreased integrity of fronto-parietal white matter mediated age-related increases in switch costs (Gold et al., 2008
). Diffusivity in anterior regions (O’Sullivan et al., 2001
) and anisotropy in widespread cortical white matter (Grieve et al., 2007
) has been associated with performance on the Trail making test, which requires alternation between numeric and letter stimuli, although in other samples (e.g., Charlton et al., 2006
) no such associations were found.
In accord with other studies, we found no direct associations between regional or global indices of white matter integrity and perseveration on WCST (Charlton et al., 2007; O’Sullivan et al., 2001
). On the other hand, in some samples, age differences in WCST performance have been related to white matter pathology (white matter hyperintensity burden) and prefrontal cortex volume (Gunning-Dixon & Raz, 2000
; Head et al., 2002
; Raz et al., 1998
). That discrepancy across studies may reflect difference in sensitivity of various imaging approaches. It is possible that the type of perseverative deficits that are observed on WCST become apparent only when the white matter undergoes gross changes expressed in volume loss. The diffusion-based indices of white matter integrity may reveal deficits at an earlier stage and thus they do not show the associations with WCST performance. Taken together with the functional imaging literature (Colette & van der Linden, 2002), the current results indicate that age-related differences in executive functions do not dependent upon intact prefrontal white matter alone. Rather, they reflect the integrity of a widely distributed network of white matter connections, especially fronto-parietal networks, but also cerebellar connections. Because multiple executive functions do not show a clear “frontal” pattern of structure-function associations, a frequently used reification of executive functions with prefrontal regions is unwarranted (Buckner, 2004
; Glisky et al., 1995
; Greenwood, 2000
; Stuss & Alexander, 2002; Tisserand & Jolles, 2003
; West, 1996
). Because longitudinal studies show that posterior association regions, e.g., inferior parietal lobule, are just as sensitive to aging as prefrontal regions (Raz et al., 2005
), and because executive functions indeed depend on both prefrontal and posterior parietal cortices, the term “associative regional aging” may be more appropriate than “frontal aging” hypothesis.
Episodic memory showed a simpler pattern of regional microstructural associations than other functions. In this sample, age-related reductions in white matter microstructure in the internal capsule, temporal stem, and superior/parietal regions were associated with reduced performance on several memory tasks. These regions represent fibers in the uncinate fasciculus, which project anteriorly to the frontal cortex and posteriorly via the IFO and ILF to the occipital cortex. Parietal association cortex is connected via the SLF and SFO to frontal, temporal, and occipital cortex. Hence, intact white matter across a distributed network may underlie better memory in older adults. These findings are not directly comparable to the other studies that fail to find diffusion-based correlates of mnemonic performance (Deary et al., 2006
; Shenkin et al., 2005
; Grieve et al., 2007
). In those studies, coarse sections of the white matter were sampled and the regions that we found associated with memory were not measured. In two studies of episodic memory, FA in the genu of the corpus callosum of older adults correlated with recruitment of the fMRI signal in the frontal regions (Persson et al., 2006
) and reduced FA in the genu and pericallosal frontal regions was associated with speed of episodic retrieval (Bucur et al., 2007).
A strength of the current study is the use of manual ROI placement in native space for each participant, which allowed us to maximize neuroanatomical validity and to avoid the misregistration, segmentation, and smoothing errors that can occur in automated or semiautomated techniques (Jones et al., 2005
), as well as other limitations of voxel-based methods that may be especially apparent in aging brains (Kennedy et al., 2008
; Sullivan & Pfefferbaum, 2006
; Tisserand et al., 2002
). However, manual methods limit the choice of regions to a priori
hypothesized selections, a trade-off we chose. Another potential limitation of this study is that although we were not interested in sex effects per se
, because the women in this sample were on average younger than the men, sex differences are difficult to interpret when they occurred, especially in a relatively small sample, albeit larger than the median N
= 38 participants in the extant studies. Further, given the large number of statistical trends found in the analyses, in larger samples additional structure-function associations may be revealed. The present study relied on legacy data we acquired with an older implementation of the DTI approach, and application of new advances in DTI methods may reveal findings that were missed in this study. Finally, the cross-sectional design implemented in this study limits the assessment of change to estimation based on age differences. True age-related changes can only be gauged by a longitudinal study, currently underway in our laboratory.
Our findings and those of others suggest that degradation of callosal fibers, both anterior and posterior, may reduce the likelihood of successful bilateral compensation in older adults (Cabeza, 2002
; Dennis & Cabeza, 2008
; Reuter-Lorenz, 2002
; Tulving et al., 1994
). We have also shown that white matter degradation along the major association pathways may lead to a sufficient disconnection that hampers transmission between cortical regions that provide neural support for different aspects of cognition. If maintenance of optimal cognitive performance in older adults depends upon compensatory “rerouting” of the information flow, then such a process is significantly jeopardized by reduced anisotropy and increased diffusivity in these regions. In sum, the current study demonstrates that both aging and degradation of the regional associative white matter exert independent additive effects on multiple domains of cognition, in support of a disconnection hypothesis of cognitive aging. The observed distinct and dissociable relations between structural characteristics of circumscribed brain regions and specific cognitive functions indicate that cognitive aging is unlikely to stem from a single factor.