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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.

SUBMITTER: Taylor WD

PROVIDER: S-EPMC3674224 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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The vascular depression hypothesis: mechanisms linking vascular disease with depression.

Taylor W D WD Aizenstein H J HJ Alexopoulos G S GS

Molecular psychiatry 20130226 9

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. ...[more]

PMID: 23439482

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Project description:BackgroundThe clinical correlation between erectile dysfunction (ED) and depression has been revealed in cumulative studies. However, the evidence of shared mechanisms between them was insufficient. This study aimed to explore common transcriptomic alterations associated with ED and depression.Materials and methodsThe gene sets associated with ED and depression were collected from the Gene Expression Omnibus (GEO) database. Comparative analysis was conducted to obtain common genes. Using R software and other appropriate tools, we conducted a range of analyses, including function enrichment, interactive network creation, gene cluster analysis, and transcriptional and post-transcriptional signature profiling. Candidate hub crosslinks between ED and depression were selected after external validation and molecular experiments. Furthermore, subpopulation location and disease association of hub genes were explored.ResultsA total of 85 common genes were identified between ED and depression. These genes strongly correlate with cell adhesion, redox homeostasis, reactive oxygen species metabolic process, and neuronal cell body. An interactive network consisting of 80 proteins and 216 interactions was thereby developed. Analysis of the proteomic signature of common genes highlighted eight major shared genes: CLDN5, COL7A1, LDHA, MAP2K2, RETSAT, SEMA3A, TAGLN, and TBC1D1. These genes were involved in blood vessel morphogenesis and muscle cell activity. A subsequent transcription factor (TF)-miRNA network showed 47 TFs and 88 miRNAs relevant to shared genes. Finally, CLDN5 and TBC1D1 were well-validated and identified as the hub crosslinks between ED and depression. These genes had specific subpopulation locations in the corpus cavernosum and brain tissue, respectively.ConclusionOur study is the first to investigate common transcriptomic alterations and the shared biological roles of ED and depression. The findings of this study provide insights into the referential molecular mechanisms underlying the co-existence between depression and ED.

Project description:ContextResearch on vascular depression has used 2 approaches to subtype late-life depression, based on executive dysfunction or white matter hyperintensity severity.ObjectiveTo evaluate the relationship of neuropsychological performance and white matter hyperintensity with clinical response in late-life depression.DesignTwo-site, prospective, nonrandomized controlled trial.SettingOutpatient clinics at Washington University and Duke University.ParticipantsA total of 217 subjects aged 60 years or older met DSM-IV criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received vascular risk factor scores, neuropsychological testing, and magnetic resonance imaging; they were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade white matter hyperintensity lesions. Intervention Twelve weeks of sertraline treatment, titrated by clinical response. Main Outcome Measure Participants' MADRS scores over time.ResultsBaseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (P = .002), language (P = .007), working memory (P = .01), processing speed (P < .001), executive function factor scores (P = .002), and categorical Fazekas ratings (P = .05) predicted MADRS scores, controlling for age, education, age of onset, and race. Controlling for baseline MADRS scores, these factors remained significant predictors of decrease in MADRS scores, except for working memory and Fazekas ratings. Thirty-three percent of subjects achieved remission (MADRS < or =7). Remitters differed from nonremitters in baseline cognitive processing speed, executive function, language, episodic memory, and vascular risk factor scores.ConclusionsComprehensive neuropsychological function and white matter hyperintensity severity predicted MADRS scores prospectively over a 12-week treatment course with selective serotonin reuptake inhibitors in late-life depression. Baseline neuropsychological function differentiated remitters from nonremitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with vascular risk factor severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity.Trial registrationclinicaltrials.gov Identifier: NCT00045773.

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The vascular depression hypothesis: mechanisms linking vascular disease with depression.

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The vascular depression hypothesis: mechanisms linking vascular disease with depression.

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