Thomas R. Barrick

White matter damage on diffusion tensor imaging correlates with age-related cognitive decline

Background: Damage to white matter tracts, resulting in “cerebral disconnection,” may underlie age-related cognitive decline. Methods: Using diffusion tensor MRI (DTI) to investigate white matter damage, and magnetic resonance spectroscopy (MRS) to look at its underlying pathologic basis, the authors investigated the relationship between white matter structure and cognition in 106 healthy middle-aged and elderly adults. Fractional anisotropy (FA) and mean diffusivity (MD) values, whole brain white matter histograms, and regions of interest placed in the white matter of the centrum semiovale were analyzed. Correlations with executive function, working memory, and information-processing speed were performed. Results: There was a progressive reduction in FA and increase in diffusivity with age in both region of interest (r = 0.551, p < 0.001), and whole brain histograms (r = 0.625, p < 0.001). DTI values correlated with performance in all three cognitive domains. After controlling for age, DTI parameters correlated with working memory but not with the other two cognitive domains. MRS studies found a correlation of N-acetyl aspartate, a neuronal marker, with DTI parameters (r = 0.253, p < 0.05). Conclusion: The results are consistent with white matter damage due to axonal loss, causing age- related cognitive decline. Working memory may be particularly dependent on complex networks dependent on white matter connections.

White matter fiber tracking in patients with space-occupying lesions of the brain: a new technique for neurosurgical planning?

The technique of fiber tracking based on diffusion tensor imaging offers the unique possibility of localizing the white matter pathways of the brain in vivo. In patients with cerebral tumors or space-occupying lesions of the brain, these pathways are often damaged or significantly displaced. Knowledge of the exact location of the lesion with respect to clinically eloquent white matter pathways is of great value to the neurosurgeon in planning the appropriate surgical strategy. We present here preliminary findings using the fiber tracking technique in four patients with space-occupying lesions and discuss the potential and limitations of the technique for lesion localization and neurosurgical planning.

Atlas-based segmentation of white matter tracts of the human brain using diffusion tensor tractography and comparison with classical dissection.

The technique of diffusion tensor tractography is gaining increasing prominence as a non-invasive method for studying the architecture of the white matter pathways in the human brain. Numerous studies have been published that attempt to identify or reconstruct particular pathways of interest. An atlas or map of all the pathways in the white matter would be particularly useful for providing detailed anatomical data that is not available in studies based on conventional MRI data. In this paper we present a method for constructing a white matter atlas to define structures from diffusion tensor tractography by making use of the locations of the anatomical terminations of individual streamlines that pass through white matter. We show how a map of unique seed regions can be used to generate tracts of interest. This approach provides anatomical information that can be rapidly applied to MRI datasets for the clear identification of white matter tracts. We show close correspondence of the tracts generated from the atlas with tracts isolated with classical dissection of post-mortem brain tissue.

Blood–brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis

Background and aim The pathogenesis of cerebral small-vessel disease (SVD) is incompletely understood. Endothelial dysfunction has been implicated and may result in increased blood–brain barrier (BBB) permeability with leakage of blood constituents into the vessel wall and white matter. We used contrast-enhanced MRI to determine whether there was any evidence for BBB permeability in the white matter of patients with SVD, and whether this was present not only in areas of leucoaraiosis (white-matter lesions) but also in normal-appearing white matter (NAWM). Methods Subjects underwent T1 volumetric MRI before and after bolus injection of contrast. Scanning was continued for 30 min postinjection to determine the contrast-enhancement time course. The mean signal intensity change was plotted against time to calculate the area under the curve values, a parameter related to BBB permeability. Automated brain segmentation and regions of interest analysis were performed to determine ‘permeability’ in different brain compartments. Results Compared with controls (n=15), the SVD patient group (n=24) had signal changes consistent with increased BBB permeability in NAWM (p=0.033). Multivariate regression analyses identified leucoaraiosis grade as an independent predictor of these permeability related signal changes in NAWM after adjustment for age, gender, weight, brain volume, area under the curve in the internal carotid arteries and cardiovascular risk factors. Conclusion This study provides evidence for increased BBB permeability in SVD, and this is particularly seen in SVD with leucoaraiosis. Its presence in NAWM would be consistent with it playing a causal role in disease pathophysiology.

Corpus callosum damage in heavy marijuana use: preliminary evidence from diffusion tensor tractography and tract-based spatial statistics.

Heavy marijuana use has well established long term consequences for cognition and mental health, but the effect on brain structure is less well understood. We used an MRI technique that is sensitive to the structural integrity of brain tissue combined with a white matter mapping tractography technique to investigate structural changes in the corpus callosum (CC). Diffusion tensor imaging (DTI) was obtained in eleven heavy marijuana users who started using marijuana in early adolescence and eleven age matched controls. Mean diffusivity (MD) and fractional anisotropy (FA) (which measure structural integrity and tract coherence, respectively) were analysed within the corpus callosum which was spatially defined using tractography and tract-based spatial statistics (TBSS). MD was significantly increased in marijuana users relative to controls in the region of the CC where white matter passes between the prefrontal lobes. This observation suggests impaired structural integrity affecting the fibre tracts of the CC and is in keeping with previous reports of altered and diversified activation patterns in marijuana users. There was a trend towards a positive correlation between MD and length of use suggesting the possibility of a cumulative effect of marijuana over time and that a younger age at onset of use may predispose individuals to structural white matter damage. Structural abnormalities revealed in the CC may underlie cognitive and behavioural consequences of long term heavy marijuana use.

From diffusion-weighted MRI to anomalous diffusion imaging

We present a novel interpretation of non‐monoexponential diffusion‐weighted signal decay with b‐value in terms of the theory of anomalous diffusion. Anomalous diffusion is the theory of diffusing particles in environments that are not locally homogeneous, such as brain tissue. In such environments the model of restricted diffusion commonly employed in the analysis of diffusion MR data is not valid, leading to a nonlinear time dependence for the mean‐squared displacement of spins, and to a prediction of a stretched exponential form for the signal decay. We show that this prediction leads directly to a new parameter, the anomalous exponent, which may be measured from scan data and from this we can estimate a fractal dimension, dw, which categorizes the complexity of the excursions of diffusing spins. We construct images of the anomalous exponent and fractal dimension from in vivo human brain data. Distributions of exponents and dimensions are constructed in grey and white matter and cerebrospinal fluid. We observe that these distributions peak at biologically plausible values consistent with previous studies: grey matter dw = 2.366 ± 0.31, white matter dw = 2.587 ± 0.39, CSF dw = 1.970 (mode). Marked contrast is observed between grey and white matter when compared with lateral ventricle CSF. We then consider the anisotropy of the value of the anomalous exponent and define quantities analogous to the mean diffusivity and fractional anisotropy that are commonly generated from diffusion tensor images. Magn Reson Med, 2008.

White matter structural decline in normal ageing: A prospective longitudinal study using tract-based spatial statistics

Normal ageing is accompanied by a progressive decline in cognitive function but the mechanisms for this are not fully understood. Nevertheless, the importance of white matter degeneration is supported by diffusion tensor imaging (DTI) studies, although several important questions remain about the pattern and nature of age-related white matter degeneration. Firstly, there is a lack of longitudinal data determining the rate of change in DTI parameters with age, and whether this can be detected over short time periods. Secondly, it is unclear whether observed changes are uniform across the brain or whether accelerated white matter degeneration is localised to particular brain regions, as would support the frontal-ageing hypothesis. This study uses DTI techniques to quantify structural integrity change to determine whether regional differences are apparent in the rate of degeneration during longitudinal follow-up in a sample of healthy middle aged and older adults aged between 50 and 90years. Longitudinal differences in fractional anisotropy, axial and radial diffusivity are investigated using 1D coronal slice profiles, and 2D column maps in standard space, as well as using 3D tract-based spatial statistics (TBSS) to investigate local age-related structural changes on a voxel-by-voxel basis at baseline and two-year follow-up. Results indicate that DTI can detect age-related change in white matter structure over a relatively short follow-up period and that longitudinal analyses reveal significant changes in white matter integrity throughout the brain with no evidence of accelerated decline in the frontal lobe regions during a 2year period. Common changes across different diffusion characteristics are discussed.

Multimodal MRI in Cerebral Small Vessel Disease Its Relationship With Cognition and Sensitivity to Change Over Time

Background and Purpose— Cerebral small vessel disease is the most common cause of vascular dementia. Interest in using MRI parameters as surrogate markers of disease to assess therapies is increasing. In patients with symptomatic sporadic small vessel disease, we determined which MRI parameters best correlated with cognitive function on cross-sectional analysis and which changed over a period of 1 year. Methods— Thirty-five patients with lacunar stroke and leukoaraiosis were recruited. They underwent multimodal MRI (brain volume, fluid-attenuated inversion recovery lesion load, lacunar infarct number, fractional anisotropy, and mean diffusivity from diffusion tensor imaging) and neuropsychological testing. Twenty-seven agreed to reattend for repeat MRI and neuropsychology at 1 year. Results— An executive function score correlated most strongly with diffusion tensor imaging (fractional anisotropy histogram, r=−0.640, P=0.004) and brain volume (r=0.501, P=0.034). Associations with diffusion tensor imaging were stronger than with all other MRI parameters. On multiple regression of all imaging parameters, a model that contained brain volume and fractional anisotropy, together with age, gender, and premorbid IQ, explained 74% of the variance of the executive function score (P=0.0001). Changes in mean diffusivity and fractional anisotropy were detectable over the 1-year follow-up; in contrast, no change in other MRI parameters was detectable over this time period. Conclusion— A multimodal MRI model explains a large proportion of the variation in executive function in cerebral small vessel disease. In particular, diffusion tensor imaging correlates best with executive function and is the most sensitive to change. This supports the use of MRI, in particular diffusion tensor imaging, as a surrogate marker in treatment trials.

Diffusion tensor imaging detects age related white matter change over a 2 year follow-up which is associated with working memory decline

Background: Diffusion tensor imaging (DTI) is a sensitive method for detecting white matter damage, and in cross sectional studies DTI measures correlate with age related cognitive decline. However, there are few data on whether DTI can detect age related changes over short time periods and whether such change correlates with cognitive function. Methods: In a community sample of 84 middle-aged and elderly adults, MRI and cognitive testing were performed at baseline and after 2 years. Changes in DTI white matter histograms, white matter hyperintensity (WMH) volume and brain volume were determined. Change over time in performance on tests of executive function, working memory and information processing speed were also assessed. Results: Significant change in all MRI measures was detected. For cognition, change was detected for working memory and this correlated with change in DTI only. In a stepwise regression, with change in working memory as the dependent variable, a DTI histogram measure explained 10.8% of the variance in working memory. Change in WMH or brain volume did not contribute to the model. Conclusions: DTI is sensitive to age related change in white matter ultrastructure and appears useful for monitoring age related white matter change even over short time periods.

Theory of mind associations with other cognitive functions and brain imaging in normal aging.

The study investigated age-related differences in theory of mind and explored the relationship between this ability, other cognitive abilities, and structural brain measures. A cohort of 106 adults (ages 50-90 years) was recruited. Participants completed tests of theory of mind, verbal and performance intelligence, executive function, and information processing speed and underwent structural magnetic resonance imaging (measurement of whole brain volume, volume of white matter hyperintensities, and diffusion tensor imaging of white matter integrity). Theory of mind ability declined with increasing age, and the relationship between theory of mind and age was fully mediated by performance intelligence, executive function, and information processing speed and was partially mediated by verbal intelligence. Theory of mind performance correlated significantly with diffusion tensor imaging measures of white matter integrity but not with volume of white matter hyperintensities or whole-brain volume. Theory of mind age-related decline may not be independent of other cognitive functions; it may also be particularly susceptible to changes in white matter integrity.