Lobar intracerebral haemorrhage (ICH) is associated with cerebral amyloid angiopathy (CAA) pathology. Uncertainty remains about the mechanisms leading from CAA to ICH. We investigated the distribution Show more
Lobar intracerebral haemorrhage (ICH) is associated with cerebral amyloid angiopathy (CAA) pathology. Uncertainty remains about the mechanisms leading from CAA to ICH. We investigated the distribution and characteristics of CAA, and its clinical and neuropathological associations. Participants underwent research autopsy in the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study. Neuropathologists rated tissue for CAA using standardised consensus criteria, as well as non-amyloid small vessel disease, Thal phase, and Braak stage. We compared the presence, distribution, and severity of CAA among different brain regions, and in the lobe or hemisphere affected by lobar ICH to corresponding contralateral regions. We evaluated the diagnostic accuracy of Vonsattel CAA grade on a post-mortem cortical specimen (simulating surgical biopsy) versus the reference standard of moderate-to-severe parenchymal CAA at autopsy. Among 162 participants, parenchymal CAA, meningeal CAA, and CAA-associated vasculopathy were diffusely distributed among all cerebral lobes irrespective of the ICH location, but capillary CAA showed an occipital predominance. In lobar ICH, all CAA measures did not differ between the ICH lobe or hemisphere and the contralateral unaffected region. CAA measures did not increase with age, but they were higher in carriers of APOE ε2 or ε4 alleles and in individuals with higher Thal phase or Braak stage. Using a rule-out category of Vonsattel grade ≥ 1 to diagnose CAA on a simulated cortical biopsy achieved 100% sensitivity (95%CI 93.4-100), and a rule-in category of Vonsattel grade ≥ 2 had 79.5% specificity (95%CI 63.5-90.7) versus the reference standard. The distribution and severity of parenchymal CAA, meningeal CAA, and CAA-associated vasculopathy are diffuse regardless of ICH location, indicating the need to better understand the factors underlying bleeding in CAA-affected vessels. Show less
A comprehensive computational strategy that combined QSAR modelling, molecular docking, and ADMET analysis was used to discover potential inhibitors for β-secretase 1 (BACE-1). A dataset of 1,138 comp Show more
A comprehensive computational strategy that combined QSAR modelling, molecular docking, and ADMET analysis was used to discover potential inhibitors for β-secretase 1 (BACE-1). A dataset of 1,138 compounds with established BACE-1 inhibitory activities was used to build a QSAR model using mol2vec descriptors and support vector regression. The obtained model demonstrated strong predictive performance (training set: Show less