Ante-mortem assays exist for some Transmission Spongiform Encephalopathies (TSE). These assays facilitate our understanding of disease pathology and epidemiology; however, the limitations of these ante-mortem assays include the inability to quantify protein amount, poor sensitivity, and/or limited robustness. Here, we utilize a bioinformatics approach to report on problems associated with developing a more sensitive immunoassay for TSEs including: 1) the lack of specific and sufficiently sensitive antibodies for the infectious isoform(s) of PrP(res), 2) problems associated with serial titration of PrP(res), and 3) the distribution of PrP(res) particle sizes. Overcoming these problems require more sophisticated antibody design and a creative engineering of an ultrasensitive protein assay systems for PrP(res).