The vascular depression hypothesis: mechanisms linking vascular disease with depression

Abstract

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.

Figure 1

Proposed progression of etiological processes affecting frontolimbic function. After crossing an initial threshold, vascular or other processes may serve as one of many factors that increase vulnerability to depression through compromise of affective and cognitive brain circuits. As the underlying disease process progresses, its adverse effects on the affective and cognitive circuits would likewise increase, resulting in the circuit dysfunctions that characterize depression.

Figure 2

This model links the disconnection, inflammation, and hypoperfusion processes proposed in late-life depression. Vascular disease may contribute to altered brain function characteristic of depression (dorsal hypometabolism, ventral hypermetabolism) either through structural damage adversely affecting connectivity, through perfusion deficits altering regional function, or both. Proinflammatory processes increase vascular risk but may also affect brain function through independent processes. In this model, vascular disease is an important and central contributor to LLD. Not only is vascular disease common and perhaps unavoidable in later life, but it also interacts with other pathological processes related to depression. However, vascular disease is not the only contributor to LLD. Other biological and environmental factors can increase the risk for depression by alterating neural circuit structure and function. Similarly, genetic influences may increase risk of depression by acting at multiple points, such altering function of neural circuits, changing the biological response to stress, adding to vascular risk, or predisposing to proinflammatory states.