Plasma Based Markers of [11C] PiB-PET Brain Amyloid Burden

Abstract

Changes in brain amyloid burden have been shown to relate to Alzheimer's disease pathology, and are believed to precede the development of cognitive decline. There is thus a need for inexpensive and non-invasive screening methods that are able to accurately estimate brain amyloid burden as a marker of Alzheimer's disease. One potential method would involve using demographic information and measurements on plasma samples to establish biomarkers of brain amyloid burden; in this study data from the Alzheimer's Disease Neuroimaging Initiative was used to explore this possibility. Sixteen of the analytes on the Rules Based Medicine Human Discovery Multi-Analyte Profile 1.0 panel were found to associate with [11C]-PiB PET measurements. Some of these markers of brain amyloid burden were also found to associate with other AD related phenotypes. Thirteen of these markers of brain amyloid burden – c-peptide, fibrinogen, alpha-1-antitrypsin, pancreatic polypeptide, complement C3, vitronectin, cortisol, AXL receptor kinase, interleukin-3, interleukin-13, matrix metalloproteinase-9 total, apolipoprotein E and immunoglobulin E – were used along with co-variates in multiple linear regression, and were shown by cross-validation to explain >30% of the variance of brain amyloid burden. When a threshold was used to classify subjects as PiB positive, the regression model was found to predict actual PiB positive individuals with a sensitivity of 0.918 and a specificity of 0.545. The number of APOE ϵ 4 alleles and plasma apolipoprotein E level were found to contribute most to this model, and the relationship between these variables and brain amyloid burden was explored.

Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer’s Disease

“…SAP has been previously reported as a diagnostic AD candidate biomarker in the literature [4] albeit it with conflicting direction of association [3,10,30,31]. Although we found changes in SAP to be associated with rate of decline we did not observe significant changes of SAP when comparing diagnostic groups against controls.…”

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

“…All five of these proteins have been previously identified in plasma as candidate biomarkers associated with AD disease status and/or pathology [4, 9, 22–27]. In fact α2M and C3 are two of the most reproducible plasma protein markers of AD, associating with AD-related phenotypes in five independent cohorts [5].…”

“…Due to the statistical approach used (penalized regression model), it is not possible to rule out that these proteins may have also performed as biomarkers at all three time points but were omitted from the regression model due to collinearity with another protein. Of particular interest are fibrinogen chains alpha, beta, and gamma, all of which were significantly associated with PET amyloid load at two time points, and have been identified in previous studies as biomarkers of PET amyloid load in AD cohorts [7, 27]. Furthermore fibrinogen has been shown to cross the blood-brain barrier and co-localize with amyloid plaques in AD brain tissue and AD animal models [28–30].…”

Plasma amyloid β—quo vadis?

“…AIBL, ADNI, and AddNeuroMed researchers have identified multiprotein plasma biomarker panels that together seem to identify individuals with pathological brain Ab accumulation with reasonable accuracy (Burnham et al, 2014;Kiddle et al, 2012). The different panels are, however, nonoverlapping, some protein identities are surprising, and additional validation work is needed.…”