Fiber tract‐specific white matter lesion severity Findings in late‐life depression and by AGTR1 A1166C genotype

Abstract

Past work demonstrated that late-life depression is associated with greater severity of ischemic cerebral hyperintense white matter lesions, particularly frontal lesions. However, these lesions are also associated with other neuropsychiatric deficits, so these clinical relationships may depend on which fiber tracts are damaged. We examined the ratio of lesion to nonlesioned white matter tissue within multiple fiber tracts between depressed and nondepressed elders. We also sought to determine if the AGTR1 A1166C and BDNF Val66Met polymorphisms contributed to vulnerability to lesion development in discrete tracts. 3T structural MR images and blood samples for genetic analyses were acquired on 54 depressed and 37 nondepressed elders. Lesion maps were created through an automated tissue segmentation process and applied to a probabilistic white matter fiber tract atlas allowing for identification of the fraction of the tract occupied by lesion. The depressed cohort exhibited a significantly greater lesion ratio only in the left upper cingulum near the cingulate gyrus (F1,86 = 4.62, p = 0.0344), supporting past work implicating cingulate dysfunction in the pathogenesis of depression. In the 62 Caucasian subjects with genetic data, AGTR1 C1166 carriers exhibited greater lesion ratios across multiple tracts including the anterior thalamic radiation and inferior fronto-occipital fasciculus. In contrast, BDNF Met allele carriers exhibited greater lesion ratios only in the frontal corpus callosum. Although these findings did not survive correction for multiple comparisons, this study supports our hypothesis and provides preliminary evidence that genetic differences related to vascular disease may increase lesion vulnerability differentially across fiber tracts.

Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults

“…Taylor et al (2009) reported significant increases in white matter lesion volume over a 2-year period in older adult men with the C1166 variant. A similar study from this group reported a modest association between the C1166 variant and enhanced lesion severity spanning multiple white matter tracts among nondemented elders both with and without depression (Taylor et al 2013). The results of the present study extend those of Taylor et al (2009Taylor et al ( , 2013 by demonstrating enhanced SH volume in a sample of clinically healthy (e.g., no evidence of clinical depression or dementia) older men and women.…”

“…A similar study from this group reported a modest association between the C1166 variant and enhanced lesion severity spanning multiple white matter tracts among nondemented elders both with and without depression (Taylor et al 2013). The results of the present study extend those of Taylor et al (2009Taylor et al ( , 2013 by demonstrating enhanced SH volume in a sample of clinically healthy (e.g., no evidence of clinical depression or dementia) older men and women. Furthermore, no studies have examined the functional relationship between A1166C, SH, and cognition in a healthy population.…”

“…Most notably, the A1166C polymorphism has been implicated as an independent risk factor for vascular phenotypes such as hypertension and ischemic stroke. A1166C has also been associated with white matter lesion severity in elderly populations both with and without depression (Taylor et al 2009(Taylor et al , 2013. Despite these identified relationships, an independent association between A1166C and white matter integrity has not been defined.…”

White Matter Hyperintensity Accumulation During Treatment of Late-Life Depression

“…Many magnetic resonance imaging (MRI) studies have shown that LLD is associated with demyelinating lesions, which are seen as white matter hyperintensities (WMHs) on MRI (Chen et al, 2006;Firbank et al, 2012;Herrmann et al, 2008;Krishnan et al, 2004;Taylor et al, 2005Taylor et al, , 2013. In older adults, the etiology of these lesions is largely thought to be related to ischemic disease, but other neuropathologic processes may also have a role.…”

Cingulum bundle white matter lesions influence antidepressant response in late-life depression: A pilot study

“…LLD is associated with increased WML severity in the cingulum bundle, uncinate fasciculus, and superior longitudinal fasciculus (Dalby et al, 2010; Sheline et al, 2008; Taylor et al, 2013b). Similar findings are reported in these tracts using diffusion tensor imaging to measure fiber tract structural integrity in both late-life (Sexton et al, 2012; Taylor et al, 2007) and midlife depression (Zhang et al, 2012).…”