Inflammatory Biomarkers and MRI visible Perivascular Spaces: the Framingham Heart Study

Perivascular spaces (PVS) visible on brain magnetic resonance imaging (MRI) are cerebrospinal fluid-filled spaces surrounding small penetrating cerebral blood vessels. They are considered to represent cerebral small vessel disease (CSVD) and possibly reflect a part of the brain glymphatic system (Doubal et al., 2010). PVS are seen on T2* weighted brain MRI, are observed in increasing numbers with advancing age, and have been associated with impaired cognitive function and stroke (Doubal et al., 2010). PVS are mainly observed in the basal ganglia (BG), midbrain, and centrum semiovale (CSO) regions, and their predominant topography may reflect different pathogenic mechanisms (Charidimou et al., 2017, Tsai et al., 2021). In the basal ganglia, PVS may be associated with hypertensive CSVD (Yang et al., 2017), while CSO PVS have been linked to cerebral amyloid angiopathy (CAA) (Tsai et al., 2021). However, advanced hypertensive CSVD has also been related to PVS across all brain regions (Charidimou et al., 2017).

PVS are considered as MRI markers of cerebral small vessel disease. However, their inciting or propagating mechanisms are unclear (Charidimou et al., 2017). Inflammation has been linked to the pathophysiology of various forms of cerebrovascular disease including CSVD, and clinical outcomes such as stroke and dementia (Gu et al., 2019). Inflammation may be involved in the most common forms of CSVD, including arteriolosclerosis (hypertensive vasculopathy) and CAA, and has been associated with brain MRI markers of CSVD such as covert infarcts and microbleeds (Shoamanesh et al., 2015). PVS have also been observed in close relation to active inflammatory lesions in neurological disorders strongly linked to an inflammatory response such as multiple sclerosis (Wuerfel et al., 2008).

Systemic inflammation is complex, invoking participation of several cell types and mechanisms of vascular injury such as endothelial dysfunction (Wardlaw et al., 2019), neutrophil activation (Karel et al., 2022), impaired vasodilatation, obstruction of perivascular flushing, and promotion of formation of amyloid-β (Aβ) plaques (Wardlaw et al., 2019). Notwithstanding the role of systemic inflammation in cerebral small vessel disease, little is known about the association between systemic and vascular inflammatory biomarkers and PVS in community dwelling individuals, or if there are any differences in the markers of inflammation according to PVS brain topography.

We hypothesized that inflammation is associated with MRI visible perivascular spaces and that specific markers may differ according to PVS topography. Thus, our aim was to characterize the relation between a comprehensive panel of inflammatory biomarkers reflecting systemic inflammation, vascular inflammation, and oxidative stress, and PVS, and to investigate whether there are any differences in the associations by PVS brain topography. Such knowledge may help elucidate the pathophysiology underlying PVS.

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