Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the amyloid β (Aβ) protein in the cerebral vasculature and poses a major risk factor for the development of intracerebral haemorrhages (ICH). However, only a minority of patients with CAA develops ICH (CAA-ICH), and to date it is unclear which mechanisms determine why some patients with CAA are more susceptible to haemorrhage than others. We hypothesized that an imbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) contributes to vessel wall weakening. MMP9 plays a role in the degradation of various components of the extracellular matrix as well as of Aβ and increased MMP9 expression has been previously associated with CAA. TIMP3 is an inhibitor of MMP9 and increased TIMP3 expression in cerebral vessels has also been associated with CAA. In this study, we investigated the expression of MMP9 and TIMP3 in occipital brain tissue of CAA-ICH cases (n = 11) by immunohistochemistry and compared this to the expression in brain tissue of CAA cases without ICH (CAA-non-haemorrhagic, CAA-NH, n = 18). We showed that MMP9 expression is increased in CAA-ICH cases compared to CAA-NH cases. Furthermore, we showed that TIMP3 expression is increased in CAA cases compared to controls without CAA, and that TIMP3 expression is reduced in a subset of CAA-ICH cases compared to CAA-NH cases. In conclusion, in patients with CAA, a disbalance in cerebrovascular MMP9 and TIMP3 expression is associated with CAA-related ICH.

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.

ImportanceBariatric surgery–induced weight loss is often associated with improved cognitive function. However, improvement in cognitive function is not always exhibited by all patients, and the mechanisms behind cognitive improvement remain unknown.ObjectiveTo investigate the association of changes in adipokines, inflammatory factors, mood, and physical activity with alterations in cognitive function after bariatric surgery among patients with severe obesity.Design, Setting, and ParticipantsThis cohort study included 156 patients with severe obesity (body mass index [calculated as weight in kilograms divided by height in meters squared], >35) eligible for Roux-en-Y gastric bypass, aged between 35 and 55 years, who were enrolled in the BARICO (Bariatric Surgery Rijnstate and Radboudumc Neuroimaging and Cognition in Obesity) study between September 1, 2018, and December 31, 2020. Follow-up was completed July 31, 2021; 146 participants completed the 6-month follow-up and were included in the analysis.InterventionRoux-en-Y gastric bypass.Main Outcomes and MeasuresOverall cognitive performance (based on a 20% change index of the compound z score), inflammatory factors (eg, C-reactive protein and interleukin 6 levels), adipokines (eg, leptin and adiponectin levels), mood (assessed via the Beck Depression Inventory), and physical activity (assessed with the Baecke questionnaire).ResultsA total of 146 patients (mean [SD] age, 46.1 [5.7] years; 124 women [84.9%]) completed the 6-month follow-up and were included. After bariatric surgery, all plasma levels of inflammatory markers, including C-reactive protein (median change, −0.32 mg/dL [IQR, –0.57 to –0.16 mg/dL]; P < .001) and leptin (median change, −51.5 pg/mL [IQR, –68.0 to –38.4 pg/mL]; P < .001), were lower, whereas adiponectin levels were higher (median change, 0.15 μg/mL [IQR, –0.20 to 0.62 µg/mL]; P < .001), depressive symptoms were (partly) resolved (median change in Beck Depression Inventory score, −3 [IQR, –6 to 0]; P < .001), and physical activity level was higher (mean [SD] change in Baecke score, 0.7 [1.1]; P < .001). Cognitive improvement was observed in 43.8% (57 of 130) of the participants overall. This group had lower C-reactive protein (0.11 vs 0.24 mg/dL; P = .04) and leptin levels (11.8 vs 14.5 pg/mL; P = .04) and fewer depressive symptoms at 6 months (4 vs 5; P = .045) compared with the group of participants who did not show cognitive improvement.Conclusions and RelevanceThis study suggests that lower C-reactive protein and leptin levels, as well as fewer depressive symptoms, might partly explain the mechanisms behind cognitive improvement after bariatric surgery.

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