Regional white matter volume differences in nondemented aging and Alzheimer's disease

Abstract

Accumulating evidence suggests that altered cerebral white matter (WM) influences normal aging, and further that WM degeneration may modulate the clinical expression of Alzheimer's disease (AD). Here we conducted a study of differences in WM volume across the adult age span and in AD employing a newly developed, automated method for regional parcellation of the subcortical WM that uses curvature landmarks and gray matter (GM)/WM surface boundary information. This procedure measures the volume of gyral WM, utilizing a distance constraint to limit the measurements from extending into the centrum semiovale. Regional estimates were first established to be reliable across two scan sessions in 20 young healthy individuals. Next, the method was applied to a large clinically-characterized sample of 299 individuals including 73 normal older adults and 91 age-matched participants with very mild to mild AD. The majority of measured regions showed a decline in volume with increasing age, with strong effects found in bilateral fusiform, lateral orbitofrontal, superior frontal, medial orbital frontal, inferior temporal, and middle temporal WM. The association between WM volume and age was quadratic in many regions suggesting that WM volume loss accelerates in advanced aging. A number of WM regions were further reduced in AD with parahippocampal, entorhinal, inferior parietal and rostral middle frontal WM showing the strongest AD-associated reductions. There were minimal sex effects after correction for intracranial volume, and there were associations between ventricular volume and regional WM volumes in the older adults and AD that were not apparent in the younger adults. Certain results, such as the loss of WM in the fusiform region with aging, were unexpected and provide novel insight into patterns of age associated neural and cognitive decline. Overall, these results demonstrate the utility of automated regional WM measures in revealing the distinct patterns of age and AD associated volume loss that may contribute to cognitive decline.

Figure 1

WM parcellation method. The WM parcellation method is an extension of a previously described cortical reconstruction (left panel, top), segmentation (left panel, middle) and parcellation procedure (left panel, bottom) that utilized spherical spatial normalization (Fischl et al., 1999b) to label gyral and sulcal areas throughout the brain (Desikan et al., 2006; Fischl et al., 2004). Cortical parcellations were subsequently used to assign a label to the underlying white matter by the construction of a Voronoi diagram in the WM voxels of the MR volume based on distance to the nearest cortical parcellation label (right panel, top and middle). Each Voronoi polygon then inherited the label of the parcellation unit, yielding a complete labeling of the cerebral WM. Measures were corrected for head size with an atlas-based scaling procedure (Buckner et al., 2004) for quantitative analysis.

Figure 2

Scatter plots of the volume of selected WM regions by age in nondemented and in demented individuals. There were strong associations between WM volume and age throughout several regions of the brain. Effects of dementia beyond those of age were somewhat more selective and were greatest in regions typically associated with cortical degeneration in studies of AD. See Table 3 and Table 4 for a comprehensive list of statistical effects.

Figure 3

Effects of age and dementia on WM volume split by sex and hemisphere in selected regions. All regions showing a sex differences in WM volumes within any of the three groups are presented. Most effects described in the whole group analyses were replicated across both men and women. There were relatively few regions that demonstrated a difference between men and women or interaction.

Figure 4

Ventricular volumes in YNG, OLD and AD. There was ventricular enlargement in OLD and AD compared to YNG (** p < 0.001 compared to YNG) and in AD compared to OLD (+ p < 0.005 compared to OLD). Red circles represent individual participant datapoints.

Appendix Figure 1

reprinted from (Desikan et al., 2006). A demonstration of the cortical parcellation scheme on the folded (left) and inflated (right) cortical surface with the name of each parcellation unit overlaid.