Neuropathology of Vascular Brain Health: Insights From Ex Vivo Magnetic Resonance Imaging–Histopathology Studies in Cerebral Small Vessel Disease

Sporadic cerebral small vessel disease (SVD) is a major contributor to vascular cognitive impairment and dementia in the aging human brain. On neuropathology, sporadic SVD is characterized by abnormalities to the small vessels of the brain predominantly in the form of cerebral amyloid angiopathy and arteriolosclerosis. These pathologies frequently coexist with Alzheimer disease changes, such as plaques and tangles, in a single brain. Conversely, during life, magnetic resonance imaging (MRI) only captures the larger manifestations of SVD in the form of parenchymal brain abnormalities. There appears to be a major knowledge gap regarding the underlying neuropathology of individual MRI-detectable SVD abnormalities. Ex vivo MRI in postmortem human brain tissue is a powerful tool to bridge this gap. This review summarizes current insights into the histopathologic correlations of MRI manifestations of SVD, their underlying cause, presumed pathophysiology, and associated secondary tissue injury. Moreover, we discuss the advantages and limitations of ex vivo MRI-guided histopathologic investigations and make recommendations for future studies.

MRI and CT imaging biomarkers of cerebral amyloid angiopathy in lobar intracerebral hemorrhage

Background: Cerebral amyloid angiopathy (CAA), a common cause of intracerebral hemorrhage (ICH), is diagnosed using the Boston criteria including magnetic resonance imaging (MRI) biomarkers (cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS). The simplified Edinburgh criteria include computed tomography (CT) biomarkers (subarachnoid extension (SAE) and finger-like projections (FLPs)). The underlying mechanisms and diagnostic accuracy of CT compared to MRI biomarkers of CAA are unknown. Methods: We included 140 survivors of spontaneous lobar supratentorial ICH with both acute CT and MRI. We assessed associations between MRI and CT biomarkers and the diagnostic accuracy of CT- compared to MRI-based criteria. Results: FLPs were more common in patients with strictly lobar CMB (44.7% vs 23.5%; p = 0.014) and SAE was more common in patients with cSS (61.3% vs 31.2%; p = 0.002). The high probability of the CAA category of the simplified Edinburgh criteria showed 87.2% (95% confidence interval (CI): 78.3–93.4) specificity, 29.6% (95% CI: 18.0–43.6) sensitivity, 59.3% (95% CI: 38.8–77.6) positive predictive value, and 66.4% (95%: CI 56.9–75.0) negative predictive value, 2.3 (95% CI: 1.2–4.6) positive likelihood ratio and 0.8 (95% CI 0.7–1.0) negative likelihood ratio for probable CAA (vs non-probable CAA), defined by the modified Boston criteria; the area under the receiver operating characteristic curve (AUROC) was 0.62 (95% CI: 0.54–0.71). Conclusion: In lobar ICH survivors, we found associations between putative biomarkers of parenchymal CAA (FLP and strictly lobar CMBs) and putative biomarkers of leptomeningeal CAA (SAE and cSS). In a hospital population, CT biomarkers might help rule-in probable CAA (diagnosed using the Boston criteria), but their absence is probably not as useful to rule it out, suggesting an important continued role for MRI in ICH survivors with suspected CAA.

Protective Effect of Rivaroxaban Against Amyloid Pathology and Neuroinflammation Through Inhibiting PAR-1 and PAR-2 in Alzheimer’s Disease Mice

Background: Recent studies have revealed that atrial fibrillation (AF) patients have a high risk of developing cognitive impairment, vascular dementia, and Alzheimer’s disease (AD). Some reports suggest that the application of oral anticoagulant with an appropriate dose may have a preventive effect on AD. However, which oral anticoagulant drug is more appropriate for preventing AD and the underlying mechanism(s) is still unknown. Objective: The aim of the present study was to assess the treatment effect of rivaroxaban administration as well as investigate the roles of PAR-1 and PAR-2 in the AD + CAA mice model. Methods: In the present study, we compared a traditional oral anticoagulant, warfarin, and a direct oral anticoagulant (DOAC), rivaroxaban, via long-term administration to an AD with cerebral amyloid angiopathy (CAA) mice model. Results: Rivaroxaban treatment attenuated neuroinflammation, blood-brain barrier dysfunction, memory deficits, and amyloid-β deposition through PAR-1/PAR-2 inhibition in the AD + CAA mice model compared with warfarin and no-treatment groups. Conclusion: The present study demonstrates that rivaroxaban can attenuate AD progress and can be a potential choice to prevent AD.

Harboring Cnm-Expressing Streptococcus Mutans In The Oral Cavity Relates To Both Deep and Lobar Cerebral Microbleeds

Streptococcus mutans, a major cariogenic bacterium, expressing the collagen-binding protein Cnm induces cerebrovascular inflammation, resulting in the impairment of blood brain barrier integrity followed by cerebral bleeding. We here examined the association of Cnm-positive S. mutans with cerebral microbleeds (CMBs) in acute stroke patients selected from a single-center registry database. Of 428 patients who received oral bacterial examinations among 3154 stroke patients, 326 patients who harbored S. mutans were identified. After excluding four patients without imaging data, we compared 72 patients with Cnm-positive S. mutans and 250 with Cnm-negative S. mutans. Deep, lobar and infratentorial CMBs were observed in 46 (63.9%), 36 (50.0%), 25 (34.7%) patients with Cnm-positive S. mutans and 144 (57.6%), 114 (45.6%), 101 (40.4%) with Cnm-negative S. mutans. Possession of Cnm-positive S. mutans was related to higher numbers of both deep and lobar, but not infratentorial, CMBs (risk ratios 1.57 [1.07‒2.30], deep; 5.44 [2.50‒11.85], lobar). Statistical significance persisted after adjusting for age, sex, hypertension, stroke type, National Institutes of Health Stroke Scale score, and cerebral amyloid angiopathy (risk ratios 1.61 [1.14‒2.27], deep; 5.14 [2.78‒9.51], lobar). Our study indicated that reduction of Cnm-positive S. mutans may serve as a therapeutic approach for improving the prognosis of stroke patients.

Amyloid Precursor Protein A713T Mutation in Calabrian Patients with Alzheimer’s Disease: A Population Genomics Approach to Estimate Inheritance from a Common Ancestor

Mutation A713T in the amyloid precursor protein (APP) has been linked to cases of Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA) and cerebrovascular disease. Despite its rarity, it has been observed in several families from the same geographical area, in the Calabria region in Southern Italy. Genotyping of 720,000 genome-wide SNPs with the HumanOmniExpress BeadChip was performed for six patients that were representative of apparently unrelated Calabrian families, as well as a Belgian subject of Italian descent (all with the same A713T mutation and disease). Their genomic structure and genetic relationships were analyzed. Demographic reconstruction and coalescent theory were applied to estimate the time of the most recent common ancestor (tMRCA) among patients. Results show that all A713T carriers fell into the genetic variability of Southern Italy and were not more closely related to each other than to any other healthy Calabrian individual. However, five out of seven patients shared a 1.7 Mbp-long DNA segment centered on the A713T mutation, making it possible to estimate a tMRCA for its common origin in the Calabrian region dating back over 1000 years. The analysis of affected individuals with methodologies based on human population genomics thus provides informative insights in support of clinical observations and biomedical research.