Depressive symptoms related to low fractional anisotropy of white matter underlying the right ventral anterior cingulate in older adults with atherosclerotic vascular disease.

We sought to characterize the relationship between integrity of the white matter underlying the ventral anterior cingulate (vAC) and depressive symptoms in older adults with atherosclerotic vascular disease (AVD), a condition associated with preferential degeneration of the white matter. The vAC was defined as including white matter underlying ventral Brodmann Area 24 and Brodmann Area 25, corresponding with the "subcallosal" and "subgenual" cingulate respectively. This region of interest was chosen based on the preponderance of evidence that the white matter in the region plays a critical role in the manifestation of depressive symptoms. Participants had current unequivocal diagnoses of AVD and were between 55 and 90 years-old. Fractional anisotropy (FA) was used as an index of white matter integrity and organization. Whole-brain mean diffusivity (MD) was used as an index of global white matter lesion burden. Depressive symptoms were measured using the Symptom Checklist-90-Revised (SCL-90-R) Depression Scale. Depressive symptoms were significantly related to low FA in the right vAC (r = -0.356, df = 30, p = 0.045) but not the left vAC (r = 0.024, df = 30, p = 0.896) after controlling for total brain MD (a statistical control for global white matter lesion burden). Further, depressive symptoms were significantly related to low FA in the right vAC (r = -0.361, df = 31, p = 0.039), but not the left vAC (r = 0.259, df = 31, p = 0.145) when controlled for the contralateral vAC FA. The correlation coefficients for this follow-up analysis were found to be significantly different between left and right vAC (Z = 2.310, p = 0.021). Poor white matter health in the vAC may be a biological mechanism for depressive symptoms in older adults with vascular disease. Further studies may corroborate that the right vAC plays a unique role in depressive symptom manifestation in cases where the white matter is preferentially affected, as is the case in AVD. This could lead to future targeting of the region for somatic antidepressant treatment, as well as the development of a precise approach for patients with white matter damage, which could produce significant improvement in quality of life, medical morbidity, and mortality.

Prefrontal cortex white matter tracts in prodromal Huntington disease.

Huntington disease (HD) is most widely known for its selective degeneration of striatal neurons but there is also growing evidence for white matter (WM) deterioration. The primary objective of this research was to conduct a large-scale analysis using multisite diffusion-weighted imaging (DWI) tractography data to quantify diffusivity properties along major prefrontal cortex WM tracts in prodromal HD. Fifteen international sites participating in the PREDICT-HD study collected imaging and neuropsychological data on gene-positive HD participants without a clinical diagnosis (i.e., prodromal) and gene-negative control participants. The anatomical prefrontal WM tracts of the corpus callosum (PFCC), anterior thalamic radiations (ATRs), inferior fronto-occipital fasciculi (IFO), and uncinate fasciculi (UNC) were identified using streamline tractography of DWI. Within each of these tracts, tensor scalars for fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity coefficients were calculated. We divided prodromal HD subjects into three CAG-age product (CAP) groups having Low, Medium, or High probabilities of onset indexed by genetic exposure. We observed significant differences in WM properties for each of the four anatomical tracts for the High CAP group in comparison to controls. Additionally, the Medium CAP group presented differences in the ATR and IFO in comparison to controls. Furthermore, WM alterations in the PFCC, ATR, and IFO showed robust associations with neuropsychological measures of executive functioning. These results suggest long-range tracts essential for cross-region information transfer show early vulnerability in HD and may explain cognitive problems often present in the prodromal stage. Hum Brain Mapp 36:3717-3732, 2015. © 2015 Wiley Periodicals, Inc.

Diffusion weighted imaging of prefrontal cortex in prodromal Huntington's disease.

Huntington's disease (HD) is a devastating neurodegenerative disease with no effective disease-modifying treatments. There is considerable interest in finding reliable indicators of disease progression to judge the efficacy of novel treatments that slow or stop disease onset before debilitating signs appear. Diffusion-weighted imaging (DWI) may provide a reliable marker of disease progression by characterizing diffusivity changes in white matter (WM) in individuals with prodromal HD. The prefrontal cortex (PFC) may play a role in HD progression due to its prominent striatal connections and documented role in executive function. This study uses DWI to characterize diffusivity in specific regions of PFC WM defined by FreeSurfer in 53 prodromal HD participants and 34 controls. Prodromal HD individuals were separated into three CAG-Age Product (CAP) groups (16 low, 22 medium, 15 high) that indexed baseline progression. Statistically significant increases in mean diffusivity (MD) and radial diffusivity (RD) among CAP groups relative to controls were seen in inferior and lateral PFC regions. For MD and RD, differences among controls and HD participants tracked with baseline disease progression. The smallest difference was for the low group and the largest for the high group. Significant correlations between Trail Making Test B (TMTB) and mean fractional anisotropy (FA) and/or RD paralleled group differences in mean MD and/or RD in several right hemisphere regions. The gradient of effects that tracked with CAP group suggests DWI may provide markers of disease progression in future longitudinal studies as increasing diffusivity abnormalities in the lateral PFC of prodromal HD individuals.

Characterizing white matter health and organization in atherosclerotic vascular disease: a diffusion tensor imaging study.

Atherosclerotic vascular disease (AVD) is endemic to the developed world, with known negative outcomes for cognition and brain health. The effects of AVD on the white matter fibers of the brain have not yet been studied using diffusion tensor imaging (DTI). This study examined differences in fractional anisotropy (FA) between AVD and healthy comparison (HC) participants, and described the regional patterns of FA in each group. AVD participants were hypothesized to have lower FA than HC participants, indicating abnormalities in white matter health or organization. 1.5 T diffusion tensor imaging was performed in 35 AVD and 22 HC participants. Mean FA measures were calculated for the white matter of the whole brain, as well for individual lobes. Globally and in every brain region measured except the temporal lobes, there were significant effects of group where AVD participants had lower FA values than their HC counterparts. Group differences in FA remained significant when controlled for white matter hyperintensity (WMH) volume, suggesting that FA detects white matter abnormality above and beyond what is measurable using the older WMH technique. These findings suggest a likely neural substrate underlying the changes in cognition and mood reported in atherosclerotic vascular disease patients.

White matter fractional anisotropy is inversely related to anxious symptoms in older adults with atherosclerosis.

OBJECTIVE: Clinical anxiety disorders are associated with white matter hyperintensities and diffusion abnormalities measured using diffusion tensor imaging. However, it is not known if this association extends into individuals with mild anxious symptoms without formal diagnosis, in those who are older, or in those who have atherosclerosis. The current study explores whether white matter integrity and/or organization significantly associates with anxious symptoms in older adults with and without atherosclerosis. METHODS: We recruited older adults (ages 55-90 years); 35 with clinically diagnosed atherosclerotic vascular disease (AVD) and 22 without AVD. Anxious symptoms were measured using the validated Symptom Checklist-90-Revised. Fractional anisotropy (FA), a proxy for white matter organization and health, was measured in the white matter globally, by lobe, and in several smaller regions of interest suggested by the literature. Partial correlations between anxious symptoms and FA were calculated, controlling for significant covariates. RESULTS: Participants with and without AVD did not differ in severity of anxious symptom endorsement. There was a unique inverse relationship between white matter health and anxious symptoms in the AVD participants, but not in healthy comparisons. Significant relationships were observed in the superior longitudinal fasciculus (r = -0.476, df = 32, p = 0.004), as well as the cingulum bundle, the frontal lobes, and the parietal lobes. CONCLUSIONS: Anxiety symptoms uniquely correlated with low FA in older adults with atherosclerosis. These findings may have implications for future research on the topic of anxiety in aging and vascular disease and warrant replication.

Multicenter reliability of diffusion tensor imaging.

A number of studies are now collecting diffusion tensor imaging (DTI) data across sites. While the reliability of anatomical images has been established by a number of groups, the reliability of DTI data has not been studied as extensively. In this study, five healthy controls were recruited and imaged at eight imaging centers. Repeated measures were obtained across two imaging protocols allowing intra-subject and inter-site variability to be assessed. Regional measures within white matter were obtained for standard rotationally invariant measures: fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity. Intra-subject coefficient of variation (CV) was typically <1% for all scalars and regions. Inter-site CV increased to ~1%-3%. Inter-vendor variation was similar to inter-site variability. This variability includes differences in the actual implementation of the sequence.