Fibrillar and oligomeric beta-amyloid as distinct local biomarkers for Alzheimer's disease.

Beta-amyloid is a key component of Alzheimer's disease (AD) pathology. Researchers in both academic and industry are actively pursuing the development of imaging tracers and techniques to noninvasively measure local levels of beta-amyloid in the Alzheimer's brain. This presentation summarizes recent data and discusses the opportunities and challenges of imaging plaques containing fibrillar beta-amyloid for the early diagnosis and therapeutic monitoring of amyloid targeted therapies. Further, the value and feasibility of measuring the recently described soluble oligomeric form of beta-amyloid as an alternative noninvasive biomarker is also discussed.

Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly.

Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aß measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.

Blood protein predictors of brain amyloid for enrichment in clinical trials?

BACKGROUND: Measures of neocortical amyloid burden (NAB) identify individuals who are at substantially greater risk of developing Alzheimer's disease (AD). Blood-based biomarkers predicting NAB would have great utility for the enrichment of AD clinical trials, including large-scale prevention trials. METHODS: Nontargeted proteomic discovery was applied to 78 subjects from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing with a range of NAB values. Technical and independent replications were performed by immunoassay. RESULTS: Seventeen discovery candidates were selected for technical replication. α2-Macroglobulin, fibrinogen γ-chain (FGG), and complement factor H-related protein 1 were confirmed to be associated with NAB. In an independent cohort, FGG plasma levels combined with age predicted NAB had a sensitivity of 59% and specificity of 78%. CONCLUSION: A single blood protein, FGG, combined with age, was shown to relate to NAB and therefore could have potential for enrichment of clinical trial populations.

Compact Fluorescence and White Light Imaging System for Intraoperative Visualization of Nerves.

Fluorescence image guided surgery (FIGS) allows intraoperative visualization of critical structures, with applications spanning neurology, cardiology and oncology. An unmet clinical need is prevention of iatrogenic nerve damage, a major cause of post-surgical morbidity. Here we describe the advancement of FIGS imaging hardware, coupled with a custom nerve-labeling fluorophore (GE3082), to bring FIGS nerve imaging closer to clinical translation. The instrument is comprised of a 405 nm laser and a white light LED source for excitation and illumination. A single 90 gram color CCD camera is coupled to a 10 mm surgical laparoscope for image acquisition. Synchronization of the light source and camera allows for simultaneous visualization of reflected white light and fluorescence using only a single camera. The imaging hardware and contrast agent were evaluated in rats during in situ surgical procedures.