Rebecca A. Charlton

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 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.

A structural equation modeling investigation of age-related variance in executive function and DTI measured white matter damage

Cognitive changes in normal aging have been explained by the frontal-executive hypothesis, but the assumptions made by this hypothesis concerning the neurobiological causes are still a matter of debate. Executive functions (EF) may activate neural networks that include disparate grey matter regions, and rely on the integrity of white matter connections. In 118 adults (50-90 years old) from the GENIE study, white matter integrity was measured using diffusion tensor imaging, and information processing speed, fluid intelligence and EF were assessed. A theory-driven structural equation model was developed to test associations between variables. The model was revised, removing non-significant paths. The adjusted model explained well the covariance in our data; and suggested that the reduction in white matter integrity associated with age directly affected only working memory. Fluid intelligence was mediated by all measured cognitive variables. The results suggest that white matter integrity may be particularly important for abilities activating complex neural networks, as occurs in working memory. Integration of the information processing speed and frontal-executive hypotheses may provide important information regarding common, unique, and mediating factors in cognitive aging.

White matter pathways associated with working memory in normal aging.

INTRODUCTION Previous studies by our group have found that white matter integrity as determined by Diffusion Tensor Imaging (DTI) is associated with working memory decline. It has been proposed that subtle white matter integrity loss may lead to the disruption of working memory in particular because it relies on the dynamic and reiterative activity of cortico-cortical pathways. METHODS DTI and working memory measurement were acquired for 99 adults from our GENIE study of healthy middle aged and elderly individuals. Voxel-based statistics were used to identify clusters of voxels in mean diffusivity images specifically associated with variations in working memory performance. Tractography then identified the cortico-cortical white matter pathways passing through these clusters, between the temporal, parietal and frontal cortices. RESULTS Significant clusters were identified which were associated with working memory in the white matter of the temporal and frontal lobes, the cingulate gyrus, and in the thalamus. The tracts that passed through these clusters included the superior parietal lobule pathway, the medial temporo-frontal pathway, the uncinate fasciculus, the fronto-parietal fasciculus, and the cingulum. CONCLUSIONS Significant clusters were identified in the white matter that were associated with working memory performance. Tractography performed through these clusters identified white matter fiber tracts which pass between grey matter regions known to be activated by working memory tasks and also mirror working memory pathways suggested by previous functional connectivity imaging.

Diffusion tensor imaging of thalamus correlates with cognition in CADASIL without dementia

Background: Executive dysfunction is an early feature in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and may progress to a subcortical dementia. The mechanism of cognitive impairment is incompletely understood, and correlations with T2 lesion volumes are not strong. Diffusion tensor imaging (DTI) may provide a better index of white matter tract damage. Previous DTI studies in CADASIL demonstrated abnormalities in normal-appearing white matter, thalamus, and putamen and correlations with the Mini-Mental State Examination (MMSE). Objectives: To determine whether DTI abnormalities could be identified in nondemented patients with CADASIL and whether these correlated particularly strongly with executive function. Methods: Eighteen CADASIL subjects underwent DTI and cognitive assessment, including tests of several aspects of executive function. DTI was also performed on 12 age-matched control subjects. Results: Mean diffusivity was increased in white matter lesions, normal-appearing white matter, and normal-appearing gray matter (thalamus, putamen, and globus pallidus). A composite score of executive function correlated with diffusivity in both normal-appearing gray matter (r = −0.73, p = 0.002) and white matter (r = −0.68, p = 0.004). The strongest correlation for gray matter was for the thalamus (r = −0.66, p = 0.004); this remained after controlling for age, gender, and T2 lesion volumes. Correlations with MMSE were much weaker, and there was no correlation between T2 lesion volume and the executive function score (r = −0.29, p = 0.27). Conclusions: Abnormalities of normal-appearing white and deep gray matter are present in nondemented CADASIL patients, and these DTI measurements correlate particularly strongly with executive function.

The cognitive profiles of CADASIL and sporadic small vessel disease

Background: Interpretation of treatment trials in vascular dementia is confounded by the presence of coexistent Alzheimer disease (AD) pathology. The younger onset genetic disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) offers a model of pure vascular dementia, in which such confounding is unlikely. To validate CADASILs use as a model it is important to show it results in a similar cognitive impairment. Methods: The same neuropsychological assessment was administered to patients with CADASIL (n = 34, 14 of whom had had stroke), sporadic small vessel disease (SVD) presenting with lacunar stroke and having confluent leukoaraiosis (n = 54), and healthy controls (n = 25). Results: A similar pattern of neuropsychological impairment was seen in the two diseases, with prominent early executive dysfunction. Patients with CADASIL and SVD performed worse than controls on Trails switching test (CADASIL p = 0.006; SVD p < 0.001), and on verbal fluency test (CADASIL p = 0.015; SVD p = 0.004). The SVD group also performed worse on immediate (p = 0.050) and delayed (p = 0.049) memory. When only patients with CADASIL with stroke were included in analysis with SVD subjects, all of whom had had stroke, a very similar cognitive profile was seen. The only difference was on verbal fluency, where CADASIL subjects performed worse (p = 0.044). Conclusion: Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and small vessel disease show a similar pattern of cognitive deficits. This suggests that CADASIL provides a model of pure vascular dementia relevant for sporadic small vessel disease vascular dementia.

Imaging age-related cognitive decline: A comparison of diffusion tensor and magnetization transfer MRI

To determine which MR technique was the most sensitive to age‐related white matter damage. We compared both diffusion tensor imaging (DTI) and magnetization transfer (MT) maps to determine which technique correlated most strongly with cognitive function in a middle‐aged and elderly community population.