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.
Highlights
The failure of several clinical trials targeting brain amyloid deposition in patients with Alzheimers disease (AD) has led to the suggestion that these agents may be useful if targeted at older individuals in pre-symptomatic stages of the disease [1,2]
The two methods that are most likely to be useful in estimating levels of brain amyloid burden are in vivo imaging with positron emission tomography (PET) using radioligands binding to fibrillar amyloid beta (Ab), such as [11C] Pittsburgh B compound (PiB), and assays of Ab levels in cerebrospinal fluid (CSF) [4,5]
In the slightly larger Alzheimer’s Disease Neuroimaging Initiative (ADNI)-PiB PET cohort, whose sample characteristics are shown in Table S1, brain amyloid burden was found to be significantly different across diagnostic groups (KW p-value 0.022)
Summary
The failure of several clinical trials targeting brain amyloid deposition in patients with Alzheimers disease (AD) has led to the suggestion that these agents may be useful if targeted at older individuals in pre-symptomatic stages of the disease [1,2]. The two methods that are most likely to be useful in estimating levels of brain amyloid burden are in vivo imaging with positron emission tomography (PET) using radioligands binding to fibrillar amyloid beta (Ab), such as [11C] Pittsburgh B compound (PiB), and assays of Ab levels in cerebrospinal fluid (CSF) [4,5]. Both these methods have inherent drawbacks that limit their utility as screening tools, especially in resource-poor settings. Noninvasive screening method that accurately estimates brain amyloid burden would fulfil a critical unmet need in the care of the elderly
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