Association between hypertension and neurovascular inflammation in both normal-appearing white matter and white matter hyperintensities

Abstract

The major vascular cause of dementia is cerebral small vessel disease (SVD), including white matter hyperintensities (WMH) amongst others. While the underlying pathology of SVD remains unclear, chronic hypertension and neuroinflammation are recognized as important risk factors for SVD and for the conversion of normal-appearing white matter (NAWM) to WMH. Unfortunately, most studies investigating the role of neuroinflammation in WMH relied on peripheral blood markers, e.g., markers for systemic or vascular inflammation, as a proxy for inflammation in the brain itself. However, it is unknown whether such markers accurately capture inflammatory changes within the cerebral white matter. Therefore, we aimed to comprehensively investigate the impact of hypertension on perivascular- and neuroinflammation in both WMH and NAWM. We conducted high field brain magnetic resonance imaging (MRI), followed by (immuno-)histopathological staining of neuroinflammatory markers on human post-mortem brains of elderly people with a history of hypertension (n = 17) and age-matched normotensive individuals (n = 5). MRI images were co-registered to (immuno-)histopathological data including stainings for microglia and astroglia to assess changes in MRI-based WMH at microscopic resolution. Perivascular inflammation was carefully assessed based on the severity of perivascular astrogliosis of the smallest vessels throughout white matter regions. Hypertension was associated with a larger inflammatory response in both WMH and NAWM. Notably, the presence of close-range perivascular inflammation was twice as common among those with hypertension than in controls both in WMH and NAWM, suggesting that neurovascular inflammation is critical in the etiology of WMH. Moreover, a higher degree of microglial activation was related to a higher burden of WMH. Our results indicate that neuro(vascular)inflammation at the level of the brain itself is involved in the etiology of WMH. Future therapeutic strategies focusing on multitarget interventions including antihypertensive treatment as well as neuroinflammation may ameliorate WMH progression.

Vascular and neural transcriptomics reveal stage-dependent pathways to inflammation and cognitive dysfunction in a rat model of hypertension

“…spontaneously hypertensive rats or angiotensin II-induced hypertensive mice) and particularly in the human brain of hypertensive individuals to generalize the concept and rule out genetic contributions in the SHRSP model [16, 69]. Lastly the integration of our results into human literature remains difficult since longitudinal studies on an individual bases are sparse [5, 13] and neuropathological studies often address advanced and end-stages of the disease [128]. This conflict can be overcome if future research focuses on characterizing the silent phase of hypertension, before structural pathologies occur.…”

The Preventive Effect of Exercise and Oral Branched-Chain Amino Acid Supplementation on Obesity-Induced Brain Changes in Ldlr−/−.Leiden Mice

“…A previous study has indicated that BCAA can initiate inflammation and oxidative stress in endothelial cells and the vasculature, which may lead to endothelial dysfunction and potentially contribute to cardiovascular disease [ 114 ]. Future studies should include additional markers of (vascular) inflammation (e.g., GFAP) to provide a more complete understanding of the underlying mechanisms of neuroinflammation and how it is affected by exercise and BCAA [ 12 ]. For example, GFAP expression has been shown to increase in astrocytes in response to inflammation [ 12 ].…”

“…Future studies should include additional markers of (vascular) inflammation (e.g., GFAP) to provide a more complete understanding of the underlying mechanisms of neuroinflammation and how it is affected by exercise and BCAA [ 12 ]. For example, GFAP expression has been shown to increase in astrocytes in response to inflammation [ 12 ]. In this study, the BCAA-supplemented exercise-treated mice behaved similarly to the HFD-fed mice with respect to the majority of neuroimaging parameters assessed, possibly because BCAA reversed exercise-induced beneficial effects on the brain.…”

“…Obesity leads to a decline in cerebrovascular health due to various risk factors such as dyslipidemia, hyperinsulinemia, and hyperglycemia, often resulting in hypertension and atherosclerosis [ 9 , 10 , 11 ]. Vascular dysfunction, in turn, is known to exacerbate vascular inflammation and microglial activation in the brain [ 12 ]. In addition, white adipose tissue (WAT) in obesity secretes pro-inflammatory cytokines, which cause systemic inflammation and damage to the microvasculature of the brain, as observed in early pathology of aging and dementia [ 13 , 14 ].…”

The importance of microvascular inflammation in ageing and age-related diseases: a position paper from the ESH working group on small arteries, section of microvascular inflammation

“…3E). Indeed, neurovascular inflammation is involved in the aetiology of WMH [258]. Similarly, cerebral small vessel disease has been identified as a key hallmark of a broad range of neurodegenerative conditions.…”