Dept. Molecular and Translational Medicine

Background: Alzheimer's disease (AD) is neuropathologically characterised by plaques containing b-amyloid (A b) and neurofibrillary tangles consisting of tau protein. A decrease in A b and an increase in tau and phospho-tau in the CSF of people with AD are the best characterised tissue fluids molecular biomarkers for AD to date. However, obtaining CSF can be problematic, and imaging techniques such as positron emission tomography imaging of b-amyloid (such as PiB PET) are costly. It is therefore of importance to develop minimally invasive peripheral markers that can better describe and predict AD neuropathology. In this study we use a pathology endophenotype study design, based upon measures of CSF Ab/Tau, with the aim to discover novel plasma based biomarkers that can predict AD pathology. Methods: Plasma biomarker discovery was undertaken in a cohort of extreme endophenotypes of pathological status, which were determined by the measurement of CSF Ab/Tau (Mulder et al, 2010). Subjects were selected with very high CSF Ab/low Tau values or very low CSF Ab/high Tau values. Validation of candidate biomarkers was performed in two independent cohorts with AD pathology endophenotypes determined by PiB PET measures of brain amyloid load (Ashton et al, 2014). Isobaric tandem mass tagging (TMT) in combination with SDS-PAGE fractionation and LC-MS/Mass spectrometry Orbitrap Velos Pro instrumentation were used to detect and quantify plasma proteins in the discovery and validation cohorts. Results: 26 plasma proteins are significantly associated with CSF-measured pathology (P < 0.05). Of these proteins, 5 show a significant association with PiB PET measures of brain amyloid load, in an independent PiB PET based cohort.The candidate biomarkers include proteins identified in earlier studies as being associated with AD, as well as novel proteins not previously identified as being related to the disease and its pathology. Conclusions: We have identified a number of candidate plasma protein markers of AD pathology in relation to CSF Ab/Tau. The association of 5 of these proteins with AD pathology has been replicated in an independent PiB PET based cohort. These markers include proteins related to the complement cascade and amyloido genic processes.

Transforming growth factor beta is a pleiotropic cytokine which plays a central role in the homeostasis of the immune system. A complex dysregulation of its signaling occurs in Loeys-Dietz syndrome, a monogenic disorder caused by mutations of transforming growth factor beta receptors type 1 or type 2, characterized by skeletal involvement, craniofacial abnormalities, and arterial tortuosity with a strong predisposition for aneurysm and dissection. In addition, several immunologic abnormalities have been described in these patients, including an increased risk of allergic disorders as well as eosinophilic gastrointestinal disorders. The occurrence of inflammatory bowel disorders has been also reported, but it is poorly documented. We describe two unrelated children with Loeys-Dietz syndrome affected by severe chronic inflammatory colitis appearing at an early age. The intestinal disease presented similar features in both patients, including a histopathological picture of non-eosinophilic chronic ulcerative colitis, striking elevation of inflammatory markers, and a distinctly severe clinical course leading to failure to thrive, with resistance to multiple immunosuppressive treatments. One of the patients also presented autoimmune thyroiditis. Our report confirms