1 MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA, 2 Departments of Psychology, Anatomy and Neurobiology, Washington University, St Louis, MO, USA, 3 Department of Radiology, Washington University, St Louis, MO, USA, 4 Department of Neurology, Washington University, St Louis, MO, USA, 5 Howard Hughes Medical Institute
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Abstract |
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Key Words: aging, atrophy, calcarine cortex, cortical thickness, dementia, executive function, magnetic resonance imaging, MRI, prefrontal cortex
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Introduction |
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Previous neuronal counting studies have suggested that degenerative changes are accelerated in specific areas of the cortex, including frontal pole and premotor cortex (Kemper, 1994). Comparisons across species led to speculation that age-related cortical changes follow a gradient, with greatest and earliest changes occurring in association areas and lesser changes occurring later in primary sensory regions (Flood and Coleman, 1988
). Although early studies postulated this atrophy to be due to neurodegeneration, several recent studies suggest that neuron number is relatively preserved in the healthy aging brain of both humans and nonhuman primates (Morrison and Hof, 1997
; Peters et al., 1998
), although alterations in neuronal morphology are evident.
Contemporary in vivo neuroimaging studies have confirmed that there are alterations in global brain morphologic properties (Jernigan et al., 1991, 2001; Pfefferbaum et al., 1994
; Blatter et al., 1995
; Raz et al., 1997
; Good et al., 2001
; Sowell et al., 2003
). These studies additionally support the view that morphological alterations may be accelerated in particular areas of the cortex described by Raz (2000
) as a patchwork pattern of differential declines and relative preservation. Preferential vulnerability of prefrontal cortex, in particular, has been demonstrated across studies, prefrontal change being greater than changes in other regions (Jernigan et al., 1991
; Raz et al., 1997
; Sowell et al., 2003
). Although this preferential vulnerability has been statistically demonstrated in certain studies (e.g. Raz et al., 1997
), the majority of MRI studies of brain aging have not directly compared regional effects to describe patterns of regional selectivity.
The specific patterns of regional change place important constraints on what may underlie cortical atrophy and how atrophy may relate to the complex constellation of cognitive changes associated with aging. One idea, originally proposed in the context of developmental myelination, is that age-associated changes are characteristic of association cortex as opposed to primary cortex (reviewed by Kemper, 1994). Consistent with this possibility, Raz (2000
) recently reported a strong relation between order of developmental myelination and degree of age-associated volumetric atrophy, with regions developing late showing the strongest age-related atrophy. Maps of cortical atrophy, as produced in the present study, provide a test of this idea, in so far as it applies to cortical atrophy patterns. More broadly construed, maps of age-associated cortical thinning provide constraints on hypotheses concerning regionally specific processes related to atrophy.
In the present study, we measured the thickness of the cerebral cortex from MR images (Dale and Sereno, 1993; Dale et al., 1999
; Fischl et al., 1999a
, 2001; Fischl and Dale, 2000
), using a technique that has been validated via histological (Rosas et al., 2002
) as well as manual measurements (Kuperberg et al., 2003
), to examine the regional patterns of age-associated cortical thinning. As a secondary question, we explored the lower age limit at which reliable effects are demonstrable. All older participants were clinically characterized to minimize the contribution of potential common medical comorbidities that could confound the interpretation of the data. We found that accelerated cortical thinning followed a pattern of progression across various brain regions that span association to primary sensory and motor areas. Tests of the reliability of this pattern yielded highly reproducible spatial patterns between independent participant samples and manual measurements confirmed the novel finding of thinning in primary sensory cortex.
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Materials and Methods |
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Two to four high-resolution MP-RAGE scans were motion corrected and averaged per participant (four volumes were averaged for all except five participants; Siemens 1.5 T Vision System, resolution 1 x 1 x 1.25 mm, TR = 9.7 ms, TE = 4 ms, FA = 10°, TI = 20 ms, TD = 200 ms) to create a single image volume with high contrast-to-noise. These acquisition parameters were empirically optimized to increase gray/white and gray/cerebrospinal fluid contrast. Cortical thickness measurements were obtained by reconstructing representations of the gray/white matter boundary (Dale and Sereno, 1993; Dale et al., 1999
) and the cortical surface and then calculating the distance between those surfaces at each point across the cortical mantle. This method uses both intensity and continuity information from the entire three-dimensional MR volume in segmentation and deformation procedures to produce representations of cortical thickness, as shown in Figure 1ac (Fischl and Dale, 2000
). The maps are created using spatial intensity gradients across tissue classes and are therefore not simply reliant on absolute signal intensity. The maps produced are not restricted to the voxel resolution of the original data thus are capable of detecting submillimeter differences between groups (Fischl and Dale, 2000
).
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Results |
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Mean global thickness measures for each group are presented in Table 1. Mean thickness measures across the surface of the cortex followed previously described histological patterns in each group. For example, gyral regions were thicker than sulcal regions and the anterior bank of the central sulcus was thicker than posterior bank as previously described in MR and post-mortem studies (Meyer et al., 1996; Fischl and Dale, 2000
).
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In order to test whether change occurred early in the agespan, an ANCOVA was performed with age and gender as independent variables while limiting the age span to participants <57 years (the YP and MP groups). This analysis revealed a significant effect of age on thickness in the left and right hemispheres: F(1,44) = 4.69 and 6.45, respectively, both P < 0.05. Global thickness declined with increasing age. There were no effects of gender or age x gender interactions for thickness in this age range. There was a significant effect of age on volume in the left and right: F(1,44) = 9.83 and 15.58, respectively, both P < 0.01. Global cortical volume declined with increasing age. There were no significant effects of gender or age x gender interactions for volume in the left and right hemispheres. Interestingly, there was a significant age effect on thickness in the left and right hemispheres when limiting the sample to participants <31 years (only YP): F(1,27) = 8.06 and 8.02, respectively, both P = 0.01. Thus, cortical thinning was present as early as middle age and was apparent in these data by the third decade of life.
Most previous neuroimaging studies have calculated total volumes, which can be factored into thickness and surface area. Thus, to further characterize the components of the morphological alterations contributing to total cortical change, we next examined age-related decline in the surface area of the cortex by ANCOVA with age and gender as independent variables. There was a decline in total cortical surface area with increasing age in the left and right hemispheres: F(1,102) = 34.25 and 36.22, respectively, both P < 0.0001 (Fig. 2e). There was an effect of gender on surface area in the left and right hemispheres F(1,102) = 41.27 and 41.60, respectively, both P < 0.0001. There were no age x gender interactions for surface area. When men and women were compared within each group by unpaired t-test, there was a gender difference in surface area in all groups with men having greater surface area than women in the left and right hemispheres in all groups examined t(29) = 2.05 and 2.01, respectively in YP, both P = 0.05, t(15) = 6.73 and 6.59 respectively in MP, both P < 0.001, and t(56) = 3.54 and 3.58, respectively in OP, both P < 0.001 (Fig. 2f). Thus, age-related reductions in both thickness and surface area likely contribute to the age-related reductions in global volume reported in prior studies. In contrast, it remains possible that developmental differences in cortical surface area largely account for gender differences in global brain volumes.
Regional Measures and Maps of Cortical Thinning
Age-related thinning was widespread and spanned a number of cortical regions when thickness was regressed on age controlling for gender (Fig. 3). Significant thinning was found in primary sensory (occipital lobe/calcarine), primary somatosensory and motor (pre/post central gyrus and central sulcus) and association cortices (inferior lateral prefrontal cortex), with greatest statistical significance in inferior prefrontal, precentral and supramarginal regions (Fig. 3). Thinning was qualitatively variable across the cortex and was regionally variable within the major lobes (Fig. 4ad). Regions within the temporal lobe were relatively spared from significant thinning compared to other areas of the brain. Thickening of the cortex was also observed with increasing age, although very little thickening achieved statistical significance. These regions were mainly localized to the anterior cingulate and medial orbitofrontal/subcallosal cortex.
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Discussion |
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Regionally, certain results, including prominent thinning of prefrontal cortex (Raz et al., 1997; Jernigan et al., 2001
; Sowell et al., 2003
) and relative sparing of temporal cortex (DeCarli et al., 1994
) and parahippocampal cortex (Raz et al., 1997
), converged with previous findings from volumetric neuroimaging studies. However, other results were unexpected, in particular, the finding of prominent thinning in diverse regions of cortex including frontal cortex near the primary motor and premotor areas and calcarine cortex near striate cortex. Thus, the present results do not support theories of cortical aging proposing that atrophy progresses from association to primary sensory/motor cortex. Neither do the data support theories suggesting that cortical atrophy progresses in reverse order to maturational development. Rather, the present results suggest that atrophy is widespread across the cortex and may begin early in adulthood. These issues are discussed below along with potential caveats associated with the methods.
Patterns of Thinning and Relation to Theories of Cognitive Aging
The central result of this paper is the regional pattern of age-associated cortical thinning. By measuring change in cortical thickness along the continuous cortical surface, areas of accelerated thinning and relative sparing were visualized. Figure 3 presents a description of the results in terms of those changes reaching a threshold level of statistical significance. Figure 5 presents a visualization of cortical change in terms of the absolute magnitude of age-associated thinning (in mm/decade). We do not see a clear relationship with previously established patterns of morphology or function in these maps. For example, thinning was found in regions with both large and small thickness measurements, suggesting that atrophy is not simply related to the initial thickness. Thinning was not obviously lateralized, even in regions with lateralized function such as the ventral lateral prefrontal cortex, although some subtle lateralized patterns are tentatively suggested by the data and prominent atrophy is noted in several regions that are classically considered language areas. Finally, cortical thinning did not appear to follow patterns based on the variance of the measure. Regions of the cortex with both high (ventrolateral prefrontal cortex) and low (central sulcus, primary visual cortex) morphological variability in group data showed significant thinning see Fischl and Dale (2000) for a description of group variance in thickness and curvature across the cortical surface. The direct statistical comparison of unbiased regional measures is an important aspect of brain mapping studies as discussed in recent reviews (Jernigan et al., 2003
). Our independent sample analyses demonstrated that the variability in rates of cortical thinning was reliable across samples and that rates statistically differed across regions. Thus, the data suggest a heterochronous nature of morphological alterations that is anatomically widespread and agrees with the suggestion that the aging brain exhibits a patchwork pattern of differential declines and relative preservation (Raz, 2000
). These regional patterns do not exclude a bias to thinning (atrophy) based on some pattern (or combination of patterns) of gene expression, protein synthesis, neurochemical or other physiology property (Morrison, 2000
). In this regard, the maps of regional thinning presented here may be useful toward guiding histological or molecular imaging studies attempting to elucidate such mechanisms.
Prominent cortical thinning was noted within occipital cortex, in or near primary visual cortex, as well as within the precentral gyrus. While prior studies using imaging measures have noted significant (or trends towards significant) age-associated change in occipital cortex, most volumetric studies have emphasized the relatively smaller change in occipital in contrast to prefrontal cortex (e.g. Raz et al., 1997). The present study found prominent and proportionate changes between regions within prefrontal and occipital cortex (see Fig. 5). This finding has important theoretical implications.
One hypothesis regarding structural change in aging is that regions of cortex that are late to develop are earliest to atrophy. Support for this theory has come from correlation of relative atrophy rates from volumetric studies to estimated developmental course. For example, Raz (2000) plotted the effect of age for 11 cortical regions against their rank order within Flechsigs myelination precedence (a metric of developmental mylenation of intracortical fibers). Results suggested a strong relation between the two with those regions developing late showing the strongest aging effects. The present observation of prominent cortical thinning in or near primary visual cortex and motor cortex is inconsistent with this theory and argues against a last in, first out model of aging, in so far as cortical (as opposed to subcortical or white-matter) aging effects are concerned. Evidence for a last in, first out development and degradation of myelin, such as discussed by Kemper (1994
), may still exist. In this regard, an interesting future research direction will be to link changes in white-matter to cortical atrophy. While the two may be associated, cortical atrophy and white-matter change may also reflect distinct underlying processes.
Consistent with many volumetric studies, marked thinning was noted in prefrontal cortex. Prefrontal cortex has received much attention in the field of cognitive aging as it has been noted that older adults can perform poorly on tasks that require executive functions presumed to rely on prefrontal cortex, among other structures (Moscovitch and Winocur, 1995; West, 1996
; for a critical review, see Greenwood, 2000
). Thus, it is possible that early age-related alterations in this region could contribute to age-related declines in executive processing tasks such as working memory tasks (Salat et al., 2002a
). The present data are consistent with this possibility.
One final point is that, while the present study does not specify the underlying mechanisms of cortical thinning, current literature based on histology suggests that such changes are unlikely to originate from neuronal death, as careful post-mortem studies have found relatively comparable neuronal counts between older and younger subjects (for reviews, see Dani, 1997; Morrison and Hof, 1997
), a finding that is supported by work with nonhuman primates (Peters et al., 1998
). Rather, cellular shrinkage and reduction in dendritic arborization are more likely to account for cortical thinning (Morrison and Hof, 1997
).
Methodological Considerations and Caveats
The present methods rely on a recently developed computational approach to measure the thickness of the cerebral cortex (Fischl and Dale, 2000). To make these measurements, estimates of the gray/white boundary and pial surface are constructed based on segmentation of the white matter and subsequent deformation outward to find the outer cortical surface (Dale and Sereno, 1993
; Dale et al., 1999
; Fischl et al., 1999a
,b, 2001; Fischl and Dale, 2000
). This measurement, and other related kinds of measurement (e.g. Sowell et al., 2003
), are therefore highly sensitive to the contrast of the images and can potentially produce unreliable results from one sample to the next. From a data acquisition standpoint, we minimized such concerns by acquiring and averaging two to four (most often, four) structural images per participant. None the less, direct replication of the results would be the ideal test of reliability. Figure 6 demonstrates the reliability of the method using an ROI approach and Figure 7 demonstrates that the measures are manually replicable. As another measure of reliability, we examined whole surface maps in the two independent samples described for the ROI analyses for Figure 6, by ranking all of the participants by age (sorted by sex) and placing every other participant in each group to calculate group maps. Figure 8 shows the results. The specific patterns of age-associated cortical thinning are strikingly similar between the two independent samples and also highly similar to the map produced from the full sample of participants. These results support the consistency of the findings in independent samples.
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Conclusions
Description of cortical thinning provides a potentially important means to visualize local and global atrophy. Our initial exploration of cortical thinning in non-demented aging suggests prominent atrophy in some expected regions, such as prefrontal cortex. Results also suggest surprisingly widespread cortical change that includes primary motor and visual areas. These specific patterns of cortical thinning are reliable across independent subsets of the data. Further research that extends estimates to aging in dementia may provide valuable insights into distinct forms of change associated with non-demented aging as contrast to aging associated with Alzheimer disease.
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Notes |
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Address correspondence to David H. Salat, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, 149 13th Street, Charlestown, MA 02129-2060, USA. Email: salat{at}nmr.mgh.harvard.edu.
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