Cognition in healthy aging is related to regional white matter integrity, but not cortical thickness
Introduction
Healthy aging is characterized by myriad cognitive changes. Some of the most pronounced and consistently reported deficits are on tasks that require long-term memory or that challenge cognitive control processes and working memory (Hedden and Gabrieli, 2004, Piguet and Corkin, 2007). While the pattern of age-related cognitive changes is relatively well characterized, less is known about the neural bases of age-related changes in cognition.
Age-related cognitive decline is frequently attributed to deterioration of cortical gray matter (GM) structures. Magnetic resonance imaging (MRI)-based studies point to reduced global GM volumes in OA (Allen et al., 2005, Bartzokis et al., 2001, Pfefferbaum et al., 1994, Raz et al., 1997, Raz et al., 2005, Salat et al., 1999, Walhovd et al., 2005). Several studies that examined regional effects of age found that frontal areas showed greater volumetric reduction than posterior regions (Allen et al., 2005, Bartzokis et al., 2001, Raz et al., 1997, Salat et al., 1999). Particularly notable are volumetric losses in prefrontal cortex (PFC) (Grieve et al., 2005, Raz et al., 1997, Raz et al., 2004a, Salat et al., 1999). These findings have led to the hypothesis that age-related GM loss occurs along an anterior-to-posterior gradient (Jernigan et al., 1991, Raz et al., 1997, Raz and Rodrigue, 2006, Sowell et al., 2003). While this hypothesis tends to dominate the aging literature, degeneration has also been documented in all of the major lobes of the brain (Allen et al., 2005, Bartzokis et al., 2001, Cowell et al., 1994, Raz et al., 2004a, Tisserand et al., 2002, Van Petten, 2004, Van Petten et al., 2004).
Advanced methods now allow assessment of changes in cortical thickness across the lifespan (Fischl and Dale, 2000). Similar to results from volumetric studies, cortical thickness of lateral PFC is reduced in OA. At the same time, cortical thinning is also found in the occipital lobe and precentral gyrus—areas that have not generally been associated with volumetric decline (Salat et al., 2004). The histopathological underpinnings of these macroscopic changes in cortical GM remain elusive: While early studies reported a loss of cortical neurons and decreased cell packing density (Pakkenberg and Gundersen, 1997), more advanced methods indicate that cell loss is relatively minimal in old age, overshadowed by a drastic loss of neuropil (Peters et al., 1998a).
In addition to GM degeneration, WM changes likely play an important role in explaining age-related cognitive deficits (Hinman and Abraham, 2007, Peters, 2002). Many volumetric studies have documented reduced global and regional WM volumes in OA (Allen et al., 2005, Bartzokis et al., 2001, Courchesne et al., 2000, Guttmann et al., 1998, Jernigan et al., 2001, Piguet et al., 2007, Salat et al., 1999), but see (Good et al., 2001, Pfefferbaum et al., 1994, Sullivan et al., 2004). Evidence that WM volume loss is greatest in the frontal lobes is equivocal (Allen et al., 2005, Piguet et al., 2007, Raz et al., 1997, Raz et al., 2004b, Salat et al., 1999).
Other MRI-based markers of WM degeneration include an increase in hyperintensities on T2- and proton density-weighted images, with the greatest volume of hyperintensities typically found in the WM underlying the frontal lobes (de Groot et al., 2000, DeCarli et al., 1995, Gunning-Dixon and Raz, 2000, Nordahl et al., 2006, Pfefferbaum et al., 2000, Tullberg et al., 2004, Yoshita et al., 2006). In addition, microstructural deterioration of WM has been assessed using diffusion tensor imaging (DTI), with numerous studies documenting widespread age-related decreases in fractional anisotropy (FA) (Benedetti et al., 2006, Charlton et al., 2006, Madden et al., 2004, O'Sullivan et al., 2001, Salat et al., 2005a, Sullivan and Pfefferbaum, 2003). FA measures the degree to which the diffusion of water molecules is restricted by microstructural elements, such as cell bodies, axons, or myelin and other glial cells (Beaulieu, 2002). Like WM hyperintensities, FA reductions tend to be most prominent anteriorly, such as in the genu and anterior portions of the corpus callosum and in the WM underlying PFC (Ardekani et al., 2007, Head et al., 2004, Madden et al., 2007, O'Sullivan et al., 2001, Pfefferbaum et al., 2005, Salat et al., 2005b, Sullivan and Pfefferbaum, 2006, Yoon et al., 2008). Other notable loci of decreased integrity include the internal capsule (Good et al., 2001, Salat et al., 2004), auditory pathways of the temporal lobes (Lutz et al., 2007), and cingulum bundle (Yoon et al., 2008). Postmortem studies reveal a number of pathologic factors that may cause changes in FA, including loss of small myelinated fibers (Marner et al., 2003, Tang et al., 1997) and myelin degradation (Peters, 2002), which likely contribute to volumetric change (Double et al., 1996, Guttmann et al., 1998, Ikram et al., 2008, Piguet et al., 2007).
In summary, evidence of morphological and microstructural changes in frontal areas appears consistently in the aging literature. In addition, regional alterations have been noted across wide regions of GM and WM, although the exact nature and magnitude of these changes remains a topic of debate. To explicitly test whether WM and GM exhibit similar or distinct patterns of age-related change, measures of both structures must be examined in a single group of participants. The present study achieved that goal.
A prevalent view contends that age-related decline in episodic memory is related to deterioration of the hippocampus and other medial temporal lobe structures, and that cortical losses are more highly correlated with decrements in cognitive control processes (i.e., the frontal aging hypothesis) (Tisserand and Jolles, 2003, West, 1996). While a number of studies have reported correlations between hippocampal volume and episodic memory (Golomb et al., 1996, Kramer et al., 2007), some concerns have been raised about the robustness of the effect (Van Petten, 2004). Direct evidence in favor of the frontal aging hypothesis has also been difficult to demonstrate in humans (Greenwood, 2000, Raz and Rodrigue, 2006, Van Petten et al., 2004). Diminished attention and executive function in OA have been associated with decreased global cortical volumes and reduced volumes of lateral PFC and OFC (Kramer et al., 2007, Zimmerman et al., 2006), although an inverse correlation between working memory function and OFC volume has also been reported (Salat et al., 2002). In addition, PFC volume has been inversely correlated with perseverative errors in OA (Gunning-Dixon and Raz, 2003, Raz et al., 1998). In contrast, spatial and object working memory correlated with visual cortex volume (Raz et al., 1998), but neither spatial and object or verbal working memory (Gunning-Dixon and Raz, 2003) showed significant correlations with PFC volume.
Less is known about the cognitive correlates of cortical thinning. An experiment in monkeys found that age-related cortical thinning was associated with deficits in recognition memory and overall cognitive function (Peters et al., 1998b). In humans, OA with high fluid intelligence scores had large regions of thicker cortex in the right hemisphere, most notably in posterior cingulate cortex, compared to OA with average scores (Fjell et al., 2006). In contrast, the same study found virtually no thickness differences between high and low performers on tests of executive function.
Given the distributed nature of the neural networks that support the cognitive functions that decline most with age, degradation of the connections in these networks could have a dramatic effect on the processing abilities of OA. One study of older rhesus monkeys found a correlation between measures of executive function and DTI-based measures of WM integrity in long-distance corticocortical association pathways (Makris et al., 2007). Similarly, several investigations of humans have linked deficits in processing speed, executive function, immediate and delayed recall, and overall cognition to an increased burden of periventricular WM hyperintensities in OA (Gunning-Dixon and Raz, 2000, Gunning-Dixon and Raz, 2003, Soderlund et al., 2003). WM hyperintensities have also been associated with decreased frontal lobe metabolism (DeCarli et al., 1995, Tullberg et al., 2004), and with diminished BOLD responses in PFC during performance of episodic and working memory tasks (Nordahl et al., 2006). When measured using DTI, functional correlates of decreased WM integrity included working memory impairments (Charlton et al., 2006), slowed processing speed (Bucur et al., 2008, Sullivan et al., 2006), and executive dysfunction (Deary et al., 2006, Grieve et al., 2007, O'Sullivan et al., 2001). In one study of OA, WM integrity was negatively correlated with the magnitude of the BOLD response in PFC in individuals performing an episodic memory task (Persson et al., 2006). While these studies suggest that degeneration of WM pathways may contribute to the etiology of age-related cognitive decline to an equal or greater extent than GM atrophy (Hinman and Abraham, 2007, O'Sullivan et al., 2001), a strong test of this hypothesis requires measures of GM and WM integrity in the same group of participants, and then relating those measures to cognitive test scores. To date, no study has provided a direct test of the hypothesis that cognitive performance in OA correlates more strongly with WM than with GM changes.
Our study asked two specific questions: (1) Do the patterns of age-related change differ between WM and GM structures, and (2) Are changes in discrete regions of GM and WM related to specific cognitive measures in OA? To address the first question, we used high-resolution structural MRI to obtain measures of cortical thickness and DTI-based indices of WM integrity in a single sample of young adults (YA) and OA. We hypothesized that the patterns of change in WM and GM would largely overlap, with frontal regions showing the most widespread losses. At the same time, we expected the patterns to diverge slightly, with cortical thinning also extending to primary sensory and motor cortices, while loss of WM integrity was expected to be more restricted to frontal areas. We chose not to limit our DTI analyses to WM regions and intentionally performed exploratory analyses of GM regions as well. This decision was based on emerging evidence that DTI data contain rich information about microstructural characteristics of all brain tissues (Rose et al., 2008), and may be capable of detecting age-related changes in GM structures (Abe et al., 2008). To answer the second question, our sample of OA completed a series of tasks designed to measure three cognitive domains: cognitive control, episodic memory, and semantic memory. We predicted that cognitive control and episodic memory in OA would correlate with cortical thickness in PFC and association areas of parietal and temporal lobes, respectively, as well as with the integrity of WM underlying these cortical areas. Because semantic memory tends to remain relatively stable throughout the lifespan, we did not expect to find robust structure–function correlations for this domain.
Section snippets
Participants
The participants in this study were 36 YA (16F/20M), aged 18–28 years (mean age = 21.9 ± 2.6 years), and 38 OA (20F/18M), aged 61–86 years (mean age = 70.3 ± 7.2) (Table 1). Most of the YA were recruited from the MIT and Harvard communities; OA came primarily from the MIT and Harvard alumni associations. OA had more years of education (17 ± 3.0) than YA (15 ± 2.0), due to the fact that the majority of YA had not completed their education. Our exclusion criteria were: history of neurological or psychiatric
Differences between YA and OA in WM integrity
We found widespread reductions in FA values in OA, compared to YA (Fig. 1A, yellow and red areas). As anticipated, FA was reduced in anterior regions, including the genu and anterior body of the corpus callosum, and in the WM underlying the superior and middle frontal gyri and OFC. We also noted reduced FA in the WM underlying the middle and superior temporal gyri and posterior parietal cortex. In contrast, FA values in the putamen were significantly greater in OA than in YA (blue areas).
In our
Discussion
This study addressed two open questions about cognitive aging: (1) Do the distributions of age-related change in cortical thickness and WM integrity overlap, or are these brain regions affected differently; and (2) What are the cognitive effects of these brain changes? Here we consider the specific age-related alterations in brain structure, discuss the possible implications of the brain–behavior correlations, and relate our findings to the literature on microstructural factors that may
Conclusions
Our data suggest that WM degeneration, rather than cortical (i.e., GM) thinning, may contribute more to explaining age-related deterioration of cognitive control processes and episodic memory. While healthy aging was associated with cortical thinning and loss of WM integrity, the loci of these changes were distinct. WM changes occurred in tissue underlying association cortices, whereas cortical thinning was greatest in primary sensory and motor cortices. Thus, the contribution of cortical
Acknowledgements
This work was supported by NIH grants: AG021525 (SC), K01 AG24898 (DS), and T32 GM007484 (DZ). Imaging facilities at the Athinoula A. Martinos Center for Biomedical Imaging are supported by grants from the NCRR (P41RR14075) and the MIND Institute. Oliver Piguet was supported by a National Health and Medical Research Council of Australia Neil Hamilton Fairley Postdoctoral Fellowship (ID# 222909). He is now at now at the Prince of Wales Medical Research Institute, Sydney, Australia. Emily
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