In this narrative review, we present the evidence on nucleotide-binding and oligomerization (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome activation for its putative roles in the elusive pathomechanism of aging-related cerebral small vessel disease (CSVD). Although NLRP3 inflammasome-interleukin (IL)-1β has been implicated in the pathophysiology of coronary artery disease, its roles in cerebral arteriothrombotic micro-circulation disease such as CSVD remains unexplored. Here, we elaborate on the current manifestations of CSVD and its' complex pathogenesis and relate the array of activators and aberrant activation involving NLRP3 inflammasome with this condition. These neuroinflammatory insights would expand on our current understanding of CSVD clinical (and subclinical) heterogenous manifestations whilst highlighting plausible NLRP3-linked therapeutic targets.
Asymptomatic (or "silent") manifestations of cerebral small vessel disease (CSVD) are widely recognized through incidental findings of white matter hyperintensities (WMHs) as a result of magnetic resonance imaging (MRI). This study aims to examine the potential associations of surrogate markers for the evaluation of white matter integrity in CSVD among asymptomatic individuals through a battery of profiling involving QRISK2 cardiocerebrovascular risk prediction, neuroimaging, neurocognitive evaluation, and microparticles (MPs) titers. Sixty asymptomatic subjects (mean age: 39.83 ± 11.50 years) with low to moderate QRISK2 scores were recruited and underwent neurocognitive evaluation for memory and cognitive performance, peripheral venous blood collection for enumeration of selected MPs subpopulations, and 3T MRI brain scan with specific diffusion MRI (dMRI) sequences inclusive of diffusion tensor imaging (DTI). WMHs were detected in 20 subjects (33%). Older subjects (mean age: 46.00 ± 12.00 years) had higher WMHs prevalence, associated with higher QRISK2 score and reduced processing speed. They also had significantly higher mean percentage of platelet (CD62P)- and leukocyte (CD62L)-derived MPs. No association was found between reduced white matter integrity-especially at the left superior longitudinal fasciculus (LSLF)-with age and neurocognitive function; however, LSLF was associated with higher QRISK2 score, total MPs, and CD62L- and endothelial cell-derived MPs (CD146). Therefore, this study establishes these multimodal associations as potential surrogate markers for "silent" CSVD manifestations in the well-characterized cardiocerebrovascular demographic of relatively young, neurologically asymptomatic adults. Furthermore, to the best of our knowledge, this study is the first to exhibit elevated MP counts in asymptomatic CSVD (i.e., CD62P and CD62L), which warrants further delineation.