Mutation in the 3'untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy.

Aß-related cerebral amyloid angiopathy (CAA) is a major cause of primary non-traumatic brain hemorrhage. In families with an early onset of the disease, CAA can be due to amyloid precursor protein (APP) pathogenic variants or duplications. APP duplications lead to a ~1.5-fold increased APP expression, resulting in Aß overproduction and deposition in the walls of leptomeningeal vessels. We hypothesized that rare variants in the 3'untranslated region (UTR) of APP might lead to APP overexpression in patients with CAA and no APP pathogenic variant or duplication. We performed direct sequencing of the whole APP 3'UTR in 90 patients with CAA and explored the functional consequences of one previously unreported variant. We identified three sequence variants in four patients, of which a two-base pair deletion (c.*331_*332del) was previously unannotated and absent from 175 controls of same ethnicity. This latter variant was associated with increased APP expression in vivo and in vitro. Bioinformatics and functional assays showed that the APP c.*331_*332del variant affected APP messenger RNA (mRNA) structure and binding of two microRNAs (miR-582-3p and miR-892b), providing a mechanism for the observed effects on APP expression. These results identify APP 3'UTR sequence variants as genetic determinants of Aß-CAA.

[Atrial fibrillation in an acute stroke unit]. / La fibrillation atriale en unité de soins intensifs neuro- vasculaire (USINV).

Contrasting with the abundant literature dedicated to atrial fibrillation (AF) and to the use of new oral anticoagulants in this setting, very few recent studies have focused on patients with AF-associated stroke. From November 2010 to March 2011, we conducted a small prospective 4-month study in the stroke units of Lariboisière and Bicêtre hospitals. Fifty patients with FA and stroke were included (14% of all strokes), including 45 patients with cerebral infarcts (CI), 3 with transient ischemic attacks (TIA) and 2 with intracerebral hemorrhage (ICH). The results of this study, together with a review of the sparse relevant literature, underline the following points: these patients tend to be older and more frequently female than in recent clinical trials; TIAs are rare; these patients have numerous vascular risk factors and associated cerebrovascular diseases such as atheroma and leukoaraiosis; CI is often extensive and hemorrhagic; AF is discovered in a stroke unit in 40% of cases and is paroxystic in 33% of cases, with no consensus on the potential regulation; there is massive underuse of VKA in patients with known AF; rtPA intravenous thrombolysis is frequent; treatment difficulties arise in patients with AF-related CI and a history of ICH; the prognosis of VKA-related ICH is poor; the use of oral anticoagulants alone or combined with aspirin is controversial in case of AF associated with severe atheroma. Patients with AF seen in stroke units are therefore very different from those seen by cardiologists: they are older and have many vascular risk factors, stroke, and other cerebrovascular lesions, raising difficult treatment issues owing to the dual risk of embolic recurrence and symptomatic hemorrhagic transformation. In addition, contraindications to long-term VKA use are frequent. Many of these issues will again be raised with the arrival of new oral anticoagulants.