Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.

p-Coumaric acid (3-(4-hydroxyphenyl)-2-propenoic acid; 4CA), is a ubiquitous plant metabolite with antioxidant and anti-inflammatory properties. The antiplatelet activity of this compound was analysed both ex vivo and in vitro. 4-CA, administered to rabbits for 2 weeks at the dose of 5 mg/kg, mixed with food, inhibited ADP-induced platelet aggregation without affecting blood coagulation. This effect was associated with a marked increase in plasma antioxidant activity, measured as ferric reducing ability of plasma, and with the reduction of thromboxane B 2 production. The antiplatelet effect was confirmed by in vitro experiments on human blood: 4CA (500 mM and 1 mM) reduced ADP-induced platelet aggregation (55·2 (SE 4·01) % and 35·6 (SE 2·35) % relative to basal level, respectively). 4CA was able to modify platelet function, measured with PFA-100e, a shear-inducing device that simulates primary haemostasis. 4CA interfered also with arachidonic acid cascade, reducing thromboxane B 2 production and lipopolysaccharide-induced prostaglandin E 2 generation (IC 50 371 and 126 mM, respectively). The data show that 4CA is an antioxidant compound with good antiplatelet activity at doses that can be obtained with dietary intervention, suggesting possible applications for primary prevention of vascular disease.

Although mechanisms involved in the pathogenesis of asthma remain unclear, roles for oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation have been documented. Ceramide is a sphingolipid with potent proinflammatory and proapoptotic properties. This study aimed at determining whether increased formation of ceramide contributes to the development of airway inflammation and hyper-responsiveness, using a well characterized in vivo model of allergic asthmatic response and airway inflammation in ovalbumin-sensitized guinea pigs. Aerosol administration of ovalbumin increased ceramide levels and ceramide synthase activity in the airway epithelium associated with respiratory abnormalities, such as cough, dyspnea, and severe bronchoconstriction. These abnormalities correlated with nitrotyrosine formation in the airway epithelium and oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation evident by the infiltration of neutrophils and eosinophils in lung tissues, mast cell degranulation, and release of prostaglandin D 2 and proinflammatory cytokines. Inhibition of de novo ceramide synthesis with the competitive and reversible inhibitor of ceramide synthase fumonisin B1 (0.25, 0.5 and 1 mg/kg b.wt.), given i.p. daily for 4 days before allergen challenge, attenuated nitrotyrosine formation and oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation while improving the respiratory and histopathological abnormalities. These results implicate ceramide in the development of allergic asthmatic response and airway inflammation. Strategies aimed at reducing the levels of ceramide and downstream events should yield promising novel anti-asthmatic agents.

Objective: To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) or tau (FTLD-Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology and to identify clinicopathological correlates of these distinct proteinopathies. Methods: In an autopsy cohort of PPA (FTLD-TDP = 13, FTLD-Tau = 14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to 8 cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features. Results: Postmortem cortical pathology was left-lateralized in both FTLD-TDP (beta = −0.15, standard error [SE] = 0.05, p = 0.007) and FTLD-Tau (beta = −0.09, SE = 0.04, p = 0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta = −8.18, SE = 3.22, p = 0.015). Among 5 core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD-TDP, which was greater than in FTLD-Tau (F = 47.07, df = 1,17, p < 0.001), and in left midfrontal cortex (MFC) in FTLD-Tau, which was greater than in FTLD-TDP (F = 19.34, df = 1,16, p < 0.001). Postmortem pathology was inversely associated with antemortem magnetic resonance imaging cortical thickness (beta = −0.04, SE = 0.01, p = 0.007) in regions matching autopsy sampling. Irrespective of PPA syndromic variant, single-word comprehension impairment was associated with greater left OFC pathology (t = −3.72, df = 10.72, p = 0.004) and nonfluent speech with greater left MFC pathology (t = −3.62, df = 12.00, p = 0.004) among the 5 core pathology regions. Interpretation: In PPA, FTLD-TDP and FTLD-Tau have divergent anatomic distributions of left-lateralized postmortem pathology that relate to antemortem structural imaging and distinct language deficits. Although other brain regions may be implicated in neural networks supporting these complex language measures, our observations may eventually help to improve antemortem diagnosis of neuropathology in PPA.