The current study demonstrated patterns of WM atrophy in normal older adults and in patients with AD utilizing a novel, automated WM parcellation procedure. These data reveal that widespread differences in WM volume are a consequence of late, nondemented aging and that additional WM volume reduction beyond the effects of age is significant, yet somewhat more regionally selective, in AD. Profound age-associated WM differences were found in regions typically thought to be affected by age such as portions of the frontal lobe including medial orbitofrontal WM, a region that has been found to show accelerated diffusion changes in an independent sample in our prior work (Salat et al., 2005a
; Salat et al., 2005b
). The novel procedure revealed information that has not been reported in prior work. For example, although WM atrophy was apparent in regions often described to be affected with aging, significant reductions in volume were also found in regions that have not been widely previously reported, such as fusiform, inferior temporal, and middle temporal WM. Such findings may not have been possible when examining data on a lobar basis. Certain regions such as superior frontal gyrus showed WM atrophy with age as well as cortical thinning in our prior work (Salat et al., 2004
). These findings may suggest a preferential vulnerability of the superior frontal gyrus to the effects of aging although the general pattern of age-associated WM atrophy is best described as being wide-spread. Some cortical areas demonstrated evidence of preserved or even increased volume in the younger adults into the sixth decade, with a precipitous decline thereafter. These results suggest that regional WM volume is dynamically changing throughout the adult age span and may exhibit complex patterns of growth and decline.
Strong effects were apparent in some regions that have not typically been noted in prior studies of aging, such as the fusiform WM. However, recent work by Thomas and colleagues found an age associated reduction in diffusion metrics in regions within the fusiform that was associated with a decline in facial perception in older adults (Thomas et al., 2008
). These findings provide converging evidence of the effects measured with the WM parcellation technique and the potential importance of such procedures for broadly exploring the brain in a regionally unbiased manner.
Effects of AD were greatest in areas associated with cortical degeneration including entorhinal, parahippocampal, and posterior cingulated/precuneus WM, and show some overlap with our prior work examining cortical degeneration in AD (Dickerson et al., 2008
). These effects remained when limiting the sample to individuals with a CDR 0.5 (), suggesting that WM changes occur relatively early with regard to clinical presentation. Similarly, patterns of WM degeneration with aging showed some overlap (e.g. superior frontal gyrus) and some distinct effects (e.g. fusiform) compared to our prior work on age-associated cortical loss (Salat et al., 2004
). Patterns of age and AD associated WM atrophy differed, yet there was some convergence between these conditions in the vulnerability of superior frontal, middle temporal, and inferior temporal WM.
Overall, these data demonstrate the potential role of regional WM changes in age and AD associated neural and cognitive decline. One possibility is that WM degeneration contributes to the overall reduction in integrity of cognitive networks that are affected in the earliest stages of AD. These alterations could contribute to the classically described isolation of the hippocampal formation from the neocortex (Hyman et al., 1984
), as also demonstrated in our recent diffusion work (Salat et al., 2008
), and to the profound memory symptoms that are evident in the earliest stages of clinically recognizable AD. Recent functional imaging studies have revealed a more extensive network important to memory function that includes the hippocampal formation and specific, distributed cortical regions linked to the hippocampal formation (Buckner et al., 2008
; Vincent et al., 2006
; Wagner et al., 2005
). WM volume in AD was reduced throughout many of these regions consistent with AD being linked to disruption of a broad network (Buckner et al., 2008
; He et al., 2008
; Salat et al., 2008
). Given the finding that WM volume loss is apparent with very mild dementia, it is possible that this loss could have an important impact on clinical status, and could explain a portion of the variability in clinical presentation.
A number of findings uphold the utility of the presented WM parcellation method for labeling homologous regions across individuals. Test-retest reliability across two scan sessions in twenty individuals was generally good, with the majority of regions being within 5%. Variance in the volumetric measures was low across young and older adults, as well as across patients with AD. Data showed expected directional age and disease related changes. Certain findings of age and AD-related volume reduction measured using this technique are in accord with our prior studies of WM volume loss as well as DTI anisotropy studies of WM integrity (Head et al., 2004
; Salat et al., 2005a
; Salat et al., 2005b
; Salat et al., 2008
). There were associations between WMSA volume and regional WM volumes, which may suggest that volume loss is in some way associated with pathological mechanisms contributing to these lesions. However, these were modest effects, and the relative lack of associations overall may suggest that these volumetric measures provide indices of additional independent pathologic processes as has been demonstrated in prior work (Smith et al., 2000
). In contrast, there were regional associations between WM volume and ventricular volume in the OLD and AD suggesting that these regional measurements of WM volume could provide further insight into the clinical implications of ventricular enlargement which has been traditionally fairly nonspecific with regard to disease pathology. Future studies will examine this in greater detail, as well as the relationship between WM atrophy and cortical thickness to better understand the relationship between these distinct markers of degeneration. Sex differences in volumetric measures were minimal in each of the three groups, and differences found were not consistent across groups or across hemispheres, suggesting that gender has a relatively minor influence on the described measures.
Certain prior imaging and post mortem studies have noted limited or total lack of change in WM volume in aging or AD (Double et al., 1996
; Jernigan et al., 1991a
; Jernigan et al., 1991b
; Obara et al., 1994
; Rusinek et al., 1991
; Sullivan et al., 1995
; Tanabe et al., 1997
). We find preservation of WM volume in the early portion of the adult age span, and only selective regional loss of WM volume with AD. Additionally, the data suggest that younger AD may show greater regional WM volume differences compared to age matched controls compared to older AD (see ). Such an effect could make the detection of WM volume loss more difficult in smaller participant samples or with examination of a limited portion of the age span. These data demonstrate the importance of a full adult agespan study of regional effects due to the complex regional patterns measured.
It should be noted that the present WM parcellation scheme is an extension of cortical parcellation procedures. In this sense, any variation in the methods for cortical parcellation could affect the overall WM measures. For example, changes in surface area of a cortical region would affect the amount of WM labeled. It is also possible that changes in tissue composition could affect surface placement and volume measurements. A portion of the temporal lobe regions showed reduced cross-session reliability, particularly in the smaller regions. We note that that the effects were generally reliable across regions. That is, most of the effects reported were replicated in the two samples examined (men and women) across groups. Additionally, combining across regions, for example, combining the entorhinal and parahippocampal regions, improves reliability without changing the interpretation of the results. It is therefore likely that the results presented are not substantially altered by the cross-session reliability. However, future work examining the longitudinal nature of WM volume loss will require further development to enhance this reliability. The procedures for surface generation utilize local intensity gradient information (Dale et al., 1999
; Fischl and Dale, 2000
; Fischl et al., 2001
; Fischl et al., 1999a
), and thus, should not be greatly affected by absolute intensity changes as long as contrast between the two tissue classes (GM and WM) still remains. The participant sample overlaps partially with our prior work, and the finding of decreases in WM volume in certain regions that also showed cortical thinning, such as the superior frontal gyrus, suggest that the WM volume reduction measured is not a result of surface misplacement in the cortical reconstruction. We also note that the specific technical procedures used here may influence the measurements. For example, the cortical parcellation regions designate the labeling of the WM, and it is possible that different anatomical schemes would produce varying results. The Freesurfer tools for the parcellation procedure are freely available for download (surfer.nmr.mgh.harvard.edu
), and therefore, investigators could examine the reproducibility of the results in independent datasets such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI; www.adni-info.org/
) and also against alternative parcellation schemes. The data examined here are also freely available through the OASIS data release (Marcus et al., 2007
) allowing future investigators to contrast and improve upon all aspects of the present study. The present study demonstrates differential patterns of WM degeneration in aging and dementia and it is possible that WM degeneration may contribute to cognitive decline and dementia severity in AD.