Warren D. Taylor

The vascular depression hypothesis: mechanisms linking vascular disease with depression

The ‘Vascular Depression’ hypothesis posits that cerebrovascular disease may predispose, precipitate or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between LLD, vascular risk factors and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in LLD, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor, influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression, but also provide guidance on the potential repurposing of pharmacological agents that may improve LLD outcomes.

Dorsolateral prefrontal cortex and anterior cingulate cortex white matter alterations in late-life depression

BACKGROUND The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) are critical for mood regulation. Alterations in the white matter connections of these regions may impair their role in mood regulation and increase the risk of developing depression. This study used diffusion tensor imaging to examine for white matter microstructural abnormalities of these regions and of central white matter structures in late-life depression. METHODS One hundred six elderly depressed subjects and eighty-four elderly nondepressed subjects underwent clinical assessment and diffusion tensor imaging. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in regions of interest placed in the white matter of the DLPFC, ACC, corpus callosum, and internal capsule. Differences between groups were assessed, controlling for age, sex, and total cerebral volume. RESULTS After controlling for covariates, depressed subjects had significantly lower FA values in white matter of the right ACC, bilateral superior frontal gyri, and left middle frontal gyrus. There were no significant differences in ADC values. CONCLUSIONS Lower FA, representing lower tissue organization, is observed in depressed elders in the DLPFC and right ACC. These findings support the hypothesis that altered connectivity between brain regions contributes to the risk of depression.

Clinical Characteristics of Magnetic Resonance Imaging-Defined Subcortical Ischemic Depression

BACKGROUND There is a substantial body of research supporting the vascular depression hypothesis of late-life depression. To update this hypothesis so it incorporates recent research, we propose that the term subcortical ischemic vascular depression may be a more accurate representation of the disease process. We sought to investigate this diagnosis as a construct by examining differences between depressed subjects with and without magnetic resonance imaging defined subcortical ischemic vascular depression. METHODS This case-control study examined 139 depressed elderly subjects. Demographic data, psychiatric, medical, and family history, depressive symptomatology, and functional impairment were compared between groups dichotomized based on neuroimaging findings. RESULTS Seventy-five (54%) of the subjects met neuroimaging criteria for subcortical ischemic vascular depression. Age was most strongly associated with increased prevalence of subcortical ischemic vascular depression. Lassitude and a history of hypertension were also positively associated with the diagnosis; a family history of mental illness and loss of libido were negatively associated with the diagnosis. CONCLUSIONS These data support that subcortical ischemic vascular depression may be a specific syndrome from other types of late-life depression. Further research is needed to further characterize this disorder, particularly in regards to cognitive function and treatment implications.

Diffusion Tensor Imaging: Background, Potential, and Utility in Psychiatric Research

Diffusion tensor imaging is a variation of magnetic resonance imaging that measures the diffusion of water in tissues. This can help measure and quantify a tissues orientation and structure, making it an ideal tool for examining cerebral white matter and neural fiber tracts. It is only beginning to be utilized in psychiatric research. This article reviews the theory behind diffusion tensor imaging, its potential to map fiber tracts in the brain, and its recent use in psychiatric research.

Cortical White Matter Microstructural Abnormalities in Bipolar Disorder

This article reports on preliminary findings describing microstructural abnormalities in the white matter of cortical areas thought to be associated with bipolar disorder. In all, 14 patients with bipolar disorder and 21 nonpsychiatrically ill control subjects underwent MR imaging including a diffusion tensor imaging (DTI) pulse sequence (six directions, b=1000 mm2/s). DTI data were analyzed on a workstation using a program that allowed calculation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) within the following three white matter fiber tracts bilaterally: the orbital frontal cortex, and the superior and middle frontal gyri. These values were compared across patient groups. The left and right orbital frontal white matter exhibited significantly higher ADC values in bipolar subjects than control subjects on both the left (p=0.028) and right (p=0.011). Microstructural changes in the white matter of the orbital frontal areas as reflected by increased ADC values appear to be associated with bipolar disorder. Further research is needed to better understand the interaction of microstructural changes and bipolar symptoms and whether these changes are specific to bipolar disorder.

Localization of age-associated white matter hyperintensities in late-life depression

OBJECTIVE Deep white matter hyperintense lesions are associated with advanced age and late-life depression. The authors examined where age-related cerebral lesions occurred in elderly depressed and healthy control subjects. METHODS Eighty-seven depressed subjects and 47 control subjects underwent 1.5 T cranial magnetic resonance imaging (MRI). Utilizing a semiautomated method, a segmented image was created containing only white matter lesions. We created a statistical parametric map (SPM) separately for each subject group that displayed the association between lesions in any voxel and advanced age. RESULTS The SPM analysis in depressed subjects demonstrates a significant association between age and lesions found in bilateral, frontal, and left parietal regions. The analysis in control subjects found significant associations only in bilateral parieto-temporal regions, not frontal regions. CONCLUSIONS This study demonstrates a different pattern of age-related lesion location between depressed and control subjects. It further supports the theory that frontostriatal disconnection contributes to late-life depression.

Depression in the elderly

Key Clinical PointsDepression in the Elderly Late-life depression (occurring in persons 60 years of age or older) is common and is often associated with coexisting medical illness, cognitive dysfunction, or both. Depressed older adults are at increased risk for suicide. Screening for depression is important, but positive screening results should be followed by a thorough evaluation to assess patient safety and ensure that treatment is warranted. Either pharmacotherapy or psychotherapy may be used as first-line therapy. Currently available antidepressants show efficacy in depressed older populations, but older adults may be at increased risk for medication side effects. Selective serotonin-reuptake inhibitors (SSRIs) are considered first-line pharmacotherapy. Standardized psychotherapy techniques are also effective for depression in older adults.

Smaller orbital frontal cortex volumes associated with functional disability in depressed elders.

BACKGROUND Depression is associated with significant functional impairment. Recent evidence has linked the orbital frontal cortex (OFC) with depression. We examined the relationship between OFC volumes in older subjects and impairment in the basic (BADL) and instrumental (IADL) activities of daily living. METHODS The sample consisted of 81 subjects aged 60 years or older; 41 were depressed subjects and 40 healthy control subjects. In a structured interview, subjects reported their medical history and ability to perform both BADL and IADL. Subjects then had a brain magnetic resonance imaging (MRI) scan; the OFC was manually traced bilaterally using neuroanatomical landmarks. Logistic regression was used to examine the effect of OFC volume on BADL and IADL while controlling for the effects of total brain volume, subject status, medical comorbidity, and demographic factors. RESULTS Smaller OFC volumes, along with greater cognitive impairment as measured by the Mini-Mental State Examination, were significantly associated with BADL impairment. Smaller OFC volumes and being depressed were significantly associated with IADL impairment. CONCLUSIONS Smaller OFC volumes are independently associated with functional impairment, supporting its role in depression. Further studies are needed to determine how smaller OFC volumes are related to other MRI abnormalities associated with depression and functional impairment.

Hippocampus Shape Analysis and Late-Life Depression

Major depression in the elderly is associated with brain structural changes and vascular lesions. Changes in the subcortical regions of the limbic system have also been noted. Studies examining hippocampus volumetric differences in depression have shown variable results, possibly due to any volume differences being secondary to local shape changes rather than differences in the overall volume. Shape analysis offers the potential to detect such changes. The present study applied spherical harmonic (SPHARM) shape analysis to the left and right hippocampi of 61 elderly subjects with major depression and 43 non-depressed elderly subjects. Statistical models controlling for age, sex, and total cerebral volume showed a significant reduction in depressed compared with control subjects in the left hippocampus (F1,103 = 5.26; p = 0.0240) but not right hippocampus volume (F1,103 = 0.41; p = 0.5213). Shape analysis showed significant differences in the mid-body of the left (but not the right) hippocampus between depressed and controls. When the depressed group was dichotomized into those whose depression was remitted at time of imaging and those who were unremitted, the shape comparison showed remitted subjects to be indistinguishable from controls (both sides) while the unremitted subjects differed in the midbody and the lateral side near the head. Hippocampal volume showed no difference between controls and remitted subjects but nonremitted subjects had significantly smaller left hippocampal volumes with no significant group differences in the right hippocampus. These findings may provide support to other reports of neurogenic effects of antidepressants and their relation to successful treatment for depressive symptoms.

Orbitofrontal cortex volume in late life depression: influence of hyperintense lesions and genetic polymorphisms.

BACKGROUND Orbitofrontal cortex (OFC) volumetric differences have been reported in depression, but in relatively small samples. Factors associated with these differences are not well described. We examined OFC volumes in a large sample of elderly depressed and non-depressed subjects, exploring the relationship between OFC volume, 5HTTLPR genotype, apolipoprotein E (APOE) genotype and hyperintense lesion volume. We hypothesized that smaller OFC volume would be associated with depression, greater hyperintense lesion volume and severity, and APOE epsilon4 or 5HTTLPR short allele carriers. METHOD A total of 226 depressed and 144 non-depressed older subjects completed 1.5 T magnetic resonance imaging (MRI) and genotyping. OFC volumes and lesion volumes were measured using standardized methods. Lesion severity was additionally rated using the Coffey rating scale. Differences between groups were compared while controlling for age, sex and total cerebral volume; separate models added lesion measures and genetic polymorphisms. RESULTS Depressed subjects exhibited smaller OFC volumes. There was a trend for a negative association between white-matter lesion volume and OFC volume; however, rated white-matter lesion severity was significantly negatively associated with OFC volume. There was no association between gray-matter lesion measures or 5HTTLPR genotype and OFC volume. Contrary to our hypothesis, subjects who were APOE epsilon4 allele positive exhibited larger OFC volumes; in secondary analyses, this finding was limited to the non-depressed group. CONCLUSIONS Reduced OFC volumes are seen in depression and associated with greater severity of white-matter lesions. Healthy subjects who are APOE epsilon4 allele positive exhibited larger OFC volumes. This finding should be examined in other populations.