In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer’s disease

Introduction Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging. Methods Forty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer’s disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [11C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [11C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [11C]PK11195. Results Global [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (β=0.63, F(1,35)=35.24, p<0.001), deep WMH (β=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (β=0.66–0.76, t=3.90–5.58, FDR-corrected p (pFDR)=<0.001–0.002) and orbitofrontal cortex (β=0.51–0.57, t=3.53–4.30, pFDR=0.001–0.004). Conclusion Microglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD.

Participants did not have any acute infectious or chronic symptomatic systemic inflammatory disorder (e.g., systemic lupus erythematosus, rheumatoid arthritis), or MRI contraindications.
All participants had mental capacity to take part in the study and provided written informed consent. The NIMROD protocol was approved by the National Research Ethic Service's East of England Cambridge Central Committee and the UK Administration of Radioactive Substances Advisory Committee.
All scans were rated by a single trained rater (A.L.), and 30% of all scans were rated by a second rater (J.D.S.), and 20% were re-rated by the main rater (A.L.) to assess intra-rater reliability. Both were blinded to clinical and diagnostic information. Inter-rater reliability
However, CAA has been associated to global WMH burden, which has been used in the computation CAA scores. [9] Etiologically, exclusive associations have been demonstrated between deep WMH (but not periventricular WMH) and vascular risk factors including hypertension, diabetes, obesity, and atrial fibrillation, suggesting a stronger vascular underpinning and overlap with hypertensive subtype of SVD [10]. These distinctions are supported by a recent genome-wide association study demonstrating distinct genetic BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)

Statistical analysis
Normality of continuous data was tested using the Shapiro-Wilk Test. Parametric data (e.g., age, global [ 11 C]PK11195 binding, ACE-R, RAVLT) were analysed using either independent t-tests or analysis of variance (ANOVA), while nonparametric data (education, WMH volume, MMSE), were analysed using the Mann-Whitney U test. The Kruskal-Wallis test was used to analyse ordinal data such as Fazekas scores, EPVS scores, global SVD burden, CAA, and hypertensive arteriopathy scores. Chi-square tests of independence were used for group comparisons of categorical variables, i.e., the presence of CMB, lacunes, history of hypertension, hyperlipidaemia, diabetes mellitus, and smoking.