A challenging diagnosis of reversible "vascular" dementia: Cerebral amyloid angiopathy-related inflammation.

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare and treatable variant of CAA likely due to an autoimmune response directed toward beta-amyloid deposits. Cognitive and behavioral manifestations are the most common symptoms, followed by focal neurological signs, headache and seizures, associated with characteristics neuroradiological features on brain magnetic resonance imaging (MRI). We describe the clinical course, radiological features and therapeutic approach of two patients with probable CAA-ri with the aim of emphasizing the importance of an early diagnosis of this potentially reversible disease in different neurological settings, such as memory clinics and stroke units.

Transforming growth factor ß signaling perturbation in the Loeys-Dietz syndrome.

The transforming growth factor ß (TGFß) superfamily consists of multipotential secreting cytokines that mediate many key events in normal cellular growth and development, including differentiation, proliferation, motility, organization and death. TGFßs act as ligand for 3 classes of cell surface receptors, the transmembrane serine-threonine kinase receptors, TGFß receptor type I (TGFßRI) and type 2 (TGFßRII), and TGFßRIII receptors which include an ubiquitous extracellular ß-glycan and the membrane glycoprotein endoglin (CD105). Binding of TGFßs to their receptors initiates diverse cellular responses resulting in the phosphorilation of Smad proteins, which then translocate to the nucleus and regulate the transcription of target genes. Perturbation of TGFß signaling has been implicated in various human disorders including cancer, fibrosis and auto-immune diseases. Recently, mutations in TGFßR1 and TGFßR2 genes have been found in association with a continuum of clinical features with widespread vascular involvement. The extreme of clinical severity is represented by the Loeys-Dietz syndrome (LDS), an autosomal dominant disorder characterized by hypertelorism, bifid uvula, and/or cleft palate, and aggressive arteriopathy causing arterial tortuosity as well as life-threatening complications such as vascular aneurysms and dissections. Elastin disarray, loss of elastic fibre architecture and increased collagen expression in the arterial wall are the pathologic hallmark of LDS. In the present review article we will provide details on the activation of TGFß cascade, on the clinical features of LDS, as well as on the mechanisms of TGFß signaling perturbation leading to this condition and the potential role of the antagonism of TGFß activity in disease management.

Advances in antiplatelet therapy for stroke prevention: the new P2Y12 antagonists.

Thrombus formation at a site of arterial injury (eg, rupture of an atherosclerotic plaque in a carotid artery), a crucial step in the pathogenesis of cerebral ischemia, is initiated by the adhesion of platelets to the arterial wall. In vivo, activated platelets release adenosine diphosphate (ADP), whose binding to the platelet P2Y12 receptor elicits progressive and sustained platelet aggregation. As a result, this receptor has been a target for the development of clinically effective antiplatelet agents, such as the thienopyridines ticlopidine and, more recently, clopidogrel, the only two currently FDA-approved P2Y12 antagonists. Clopidogrel has a well-established role as an antithrombotic agent in the setting of ischemic stroke. However, several challenges remain, including the relatively slow onset of action of this drug and the phenomenon of clopidogrel response variability or "resistance". A number of novel P2Y12 antagonists are therefore under investigation to determine whether they can result in better or more rapid antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic (or other) side effects. These include 1) prasugrel, an orally-administered thienopyridine prodrug, 2) ticagrelor (AZD6140), an ATP analog reversible P2Y12 antagonist, 3) cangrelor, an intravenously-administered reversible P2Y12 antagonist, and 4) PRT060128. Whether the promising pharmacological profile of these drugs will be translated into clinical benefit for stroke patients will be determined by the results of clinical trials.

Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. The COL4A1 stroke syndrome.

Type IV collagens are basement membrane (BM) proteins expressed in all tissues including the vasculature. COL4A1 and COL4A2, the most abundant type IV collagens, form heterotrimers with a 2:1 stoichiometry and each heterotrimer forms a triple helix along the length of the collagenous domains. Recently, mutations in COL4A1 on chromosome 13q34, encoding the alpha1 chain of type IV collagen, have been linked to a spectrum of cerebral small-vessel disease in humans, including perinatal intracerebral hemorrhage (ICH) with consequent porencephaly, adult-onset ICH, microbleeds, lacunar strokes, and leukoaraiosis, which follows an autosomal dominant pattern of inheritance. This variable phenotype has been named the "COL4A1 stroke syndrome". In COL4A1 stroke syndrome most mutations are missense mutations involving a glycine residue, including G562E, G749S, G805R, G1130D, G1236R, G1423R, G720D, G1580R, and G755R. Mutations replacing a highly conserved hydrophobic glycine residue likely lead to synthesis of an abnormal protein with abnormal structure and inhibit heterotrimer secretion into the vascular BM, modify its structural properties (when imaged with electron microscopy BM is uneven, with inconsistent density and focal disruptions), and, thus, increase the fragility of the vessel wall when exposed to environmental factors. Although pathological changes in BM also occur in other tissues (mostly retina and kidney), the major site of vessel damage is the brain. In the present review article we will focus on the molecular basis of the COL4A1 stroke syndrome, summarize data on its variable phenotype, and explore additional questions concerning the possible genotype-phenotype correlations and the mechanisms leading to cerebral small-vessel disease in this clinically heterogeneous condition.

Common genetic markers and prediction of recurrent events after ischemic stroke in young adults.

BACKGROUND: Scarce information is available on the usefulness of new prediction markers for identifying young ischemic stroke patients at highest risk of recurrence. METHODS: The predictive effect of traditional risk factors as well as of the 20210A variant of prothrombin gene, the 1691A variant of factor V gene, and the TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR) gene on the risk of recurrence was investigated in a hospital-based cohort study of 511 ischemic stroke patients younger than 45 years followed up for a mean of 43.4 months. Outcome measures were fatal/nonfatal myocardial infarction, ischemic stroke, or TIA. Risk prediction was assessed with the use of the concordance c (c index), and the Net Reclassification Improvement (NRI). RESULTS: The risk of recurrence increased with increasing number of traditional factors (hazard ratio [HR] 2.29, 95% confidence interval [CI] 1.57-3.35 for subjects with 1 factor: HR 5.25, 95% CI 2.45-11.2 for subjects with 2), as well as with that of predisposing genotypes (HR 1.96, 95% CI 1.33-2.89 for subjects carrying 1 at-risk genotype; HR 3.83, 95% CI 1.76-8.34 for those carrying 2). The c statistics increased significantly when the genotypes were included into a model with traditional risk factors (0.696 vs 0.635, test z = 2.41). The NRI was also significant (NRI = 0.172, test z = 2.17). CONCLUSIONS: Addition of common genetic variants to traditional risk factors may be an effective method for discriminating young stroke patients at different risk of future ischemic events.

Cerebral amyloid angiopathy: a common cause of cerebral hemorrhage.

Amyloid is a term used to describe protein deposits with circumscript physical characteristics: beta-pleated sheet configuration, apple green birefringence under polarized light after Congo red staining, fibrillary structure and high insolubility. Cerebral amyloid angiopathy (CAA) defines a clinicopathological phenomenon characterized by amyloid deposition in the walls of leptomeningeal and cortical arteries, arterioles, and, less often capillaries and veins of the central nervous system. CAAs are currently classified according to the protein deposited including amyloid beta peptide (Abeta), cystatin C (ACys C), prion protein (PrP(Sc)), ABri/ADan, transthyretin (ATTR), and gelsolin (AGel). Most often amyloid deposition occurs in sporadic forms. In less common hereditary forms, a mutated variant protein or precursor protein is abnormally metabolized by proteolytic pathways in consequence of specific gene mutations, and accumulates as amyloid. The spectrum of clinical phenotypes associated with CAA-related vasculopathic changes includes both ischemic and hemorrhagic presentations, primary intracerebral hemorrhage (PICH) being probably the most well-recognized. However, in spite of accumulating data and recent progress in understanding the pathogenesis of CAA-related hemorrhage, the exact mechanisms leading to vessel rupture in these cases are yet to be established. This represents, at present, a major limitation to the identification of reliable biomarkers and the development of disease-specific treatment options. The present paper summarizes epidemiologic and clinical aspects of CAA, and highlights the presumed pathomechanisms of amyloid deposition in both sporadic and hereditary forms.