Among the MRI indices hereby assessed, micro-structural measures of the normal appearing WM were significantly correlated with information processing speed, as measured by the DSST independently of each other and of other health related factors. While all neuroimaging measures were significantly correlated with each other, there appeared to be only a partial overlap between these markers in explaining the variance of the DSST. Of the imaging markers, the MT index of normal appearing WM accounted for the greatest independent variance in DSST score, indicating that this measure may be most sensitive to cognitive slowing in the elderly. Since cognitive slowing is itself a potent index of mortality and disability, DTI and MTI may hold particular promise as mechanistic intermediate outcome markers in prevention and treatment studies of brain aging.
Our study follows from a number of previous studies of information processing speed across the age span, which suggest that micro-structural WM changes are sensitive markers for disease- and age-related cognitive decline and independent of macro-structural abnormalities such as WMH (e.g., Deary et al., 2006
; Schiavone et al., 2009
; Shimony et al., 2009
; Kochunov et al., 2010
). The current study adds to this literature by examining micro-structure of normal appearing GM in addition to normal appearing WM in a large epidemiologic sample of very old individuals. Our observation that micro-structure of the normal appearing WM is associated with processing slowing independent of GM volume is consistent with observations from cognitive aging studies (O’Sullivan et al., 2001
; Charlton et al., 2006
; Deary et al., 2006
; Schiavone et al., 2009
A strength of our study was that we examined a variety of MRI measures, including both gray and WM measures, using macro- and micro-structural indices. Thus, we were able to test the relative contributions of these markers with each other and with respect to their associations with information processing speed. This study examined one test of processing speed, the DSST because it is a widely used test in epidemiological studies, it is reliable, it is highly correlated with cognitive function. We have recently shown that this test correlates most strongly with volume of the left prefrontal cortex, as compared to other neuropsychological tests of information processing speed and executive control function (Rosano et al., 2011
A potential limitation of having multiple MR modalities is the dilution of power by the addition of more explanatory variables. One way we chose to mitigate against this limitation in the current study was by limiting the number of variables within each modality through the use of full-brain WM and GM measures. Although regional analyses are important in understanding the relative distribution of the changes across brain, the full-brain indices seem to be the single most useful measures (Nusbaum et al., 2001
; van der Flier et al., 2002
; DeCarli et al., 2005
; Whitwell et al., 2007
). Thus for comparing across measures, as we are doing here, we chose to use the full-brain markers.
There are a number of different diffusion imaging pulse sequences, which vary on, among other parameters, the number of acquired directions and the number of averages. The current study used a relatively small number of directions, 12, but chose instead to use a larger number of averages 4, while still maintaining a short acquisition time (5
min). This trade-off favors the accuracy of summary tensor measures (e.g., FA and MD) at the expense of tractographic accuracy. Our analysis approach with non-linear deformation and segmentation of tracts using individual subject’s white-matter mask, was chosen, in part, because it is particularly robust to volumetric changes. Alternative approaches, e.g., voxel-based analyses, where each subject’s DTI data is warped to standard space are more susceptible to the influence of atrophy. The MTI analysis used whole brain histogram techniques, which has two primary limitations, (1) as a full-brain measure, this lacks the anatomic specificity of ROI-based approaches, and (2) the partial volume effects at tissue boundaries could add noise to the measures.
Future studies are needed to validate the use of DTI and MTI as quantitative markers of brain integrity and to assess the effect of intervention on the progression of WM damage. The application of serial MRI with DTI and MTI in older adults may also clarify whether micro-structural age-associated differences precede brain atrophy and the formation of WMH.