Forgetful, sad and old: Do vascular cognitive impairment and depression share a common pre-disease network and how is it impacted by ageing?

Vascular cognitive impairment (VCI) and depression frequently coexist in geriatric populations and reciprocally increase disease risks. We assert that a shared pre-disease state of the psycho-immune-neuroendocrine (PINE) network model mechanistically explains bidirectional associations between VCI and depression. Five pathophysiological sub-networks are identified that are shared by VCI and depression: neuroinflammation, kynurenine pathway imbalance, hypothalamic-pituitary-adrenal (HPA) axis overactivity, impaired neurotrophic support and cerebrovascular dysfunction. These do not act independently, and their complex interactions necessitate a systems biology approach to better define disease pathogenesis. The PINE network is already established in the context of non-communicable diseases (NCDs) such as depression, hypertension, atherosclerosis, coronary heart disease and type 2 diabetes mellitus. We build on previous literature to specifically explore mechanistic links between MDD and VCI in the context of PINE pathways and discuss key mechanistic commonalities linking these comorbid conditions and identify a common pre-disease state which precedes transition to VCI and MDD. We expand the model to incorporate bidirectional interactions with biological ageing. Diathesis factors for both VCI and depression feed into this network and the culmination of shared mechanisms (on an ageing substrate) lead to a critical network transition to one or both disease states. A common pre-disease state underlying VCI and depression can provide clinicians a unique opportunity for early risk assessment and intervention in disease development. Establishing the mechanistic elements and systems biology of this network can reveal early warning or predictive biomarkers together with novel therapeutic targets. Integrative studies are recommended to elucidate the dynamic networked biology of VCI and depression over time.