The role of inflammation in cerebral small vessel disease and vascular cognitive impairment, and therapeutic implications.

Increasing evidence suggests that inflammation occurs in cerebral small vessel disease (SVD). Inflammation has been hypothesised to play a role in disease pathogenesis, and also in progression to vascular cognitive impairment and dementia (VCID), suggesting that targeting inflammation may offer a novel treatment option. In this review, we summarise the evidence that both systemic and central nervous system (CNS) inflammation occur in SVD and VCID, critically examine whether associations are causal, and review the evidence that anti-inflammatory interventions might represent possible treatments. We include coverage of sporadic SVD, cerebral amyloid angiopathy, and genetic small vessel diseases.CNS inflammation has been demonstrated in SVD both in post-mortem brains, and in vivo using positron emission tomography with radioligands targeted against the translocator surface proteins in microglia, but robust evidence showing such changes are causally related to disease progression is lacking. Peripheral inflammation can be measured in the blood using targeted assays, and more recently large scale proteomic panels. Proteins involved in coagulation, endothelial cell activation and immune cell adhesion have been associated with SVD, as well as specific cytokines, although not all findings have been replicated, and there is limited data examining whether individual proteins predict future disease progression. Genetic data can be used to inform whether such associations are likely to be casual and prioritise treatment targets. However to date, few treatment trials have investigated whether drugs that target specific inflammatory pathways can reduce SVD progression and onset of VCID, and those that have been performed have used non-specific inhibitors such as minocycline and colchicine.In summary, considerable data supports the presence of both systemic and CNS inflammation in SVD and VCID. However, whether these associations are causal remains unclear, and more longitudinal and interventional studies are required. Better understanding of the molecular basis of inflammation and immune dysfunction in SVD, also allow more precise therapeutic targeting.