Domain-specific Quantification of Prion Protein in Cerebrospinal Fluid by Targeted Mass Spectrometry.

Therapies currently in preclinical development for prion disease seek to lower prion protein (PrP) expression in the brain. Trials of such therapies are likely to rely on quantification of PrP in cerebrospinal fluid (CSF) as a pharmacodynamic biomarker and possibly as a trial endpoint. Studies using PrP ELISA kits have shown that CSF PrP is lowered in the symptomatic phase of disease, a potential confounder for reading out the effect of PrP-lowering drugs in symptomatic patients. Because misfolding or proteolytic cleavage could potentially render PrP invisible to ELISA even if its concentration were constant or increasing in disease, we sought to establish an orthogonal method for CSF PrP quantification. We developed a multi-species targeted mass spectrometry method based on multiple reaction monitoring (MRM) of nine PrP tryptic peptides quantified relative to an isotopically labeled recombinant protein standard for human samples, or isotopically labeled synthetic peptides for nonhuman species. Analytical validation experiments showed process replicate coefficients of variation below 15%, good dilution linearity and recovery, and suitable performance for both CSF and brain homogenate and across humans as well as preclinical species of interest. In n = 55 CSF samples from individuals referred to prion surveillance centers with rapidly progressive dementia, all six human PrP peptides, spanning the N- and C-terminal domains of PrP, were uniformly reduced in prion disease cases compared with individuals with nonprion diagnoses. Thus, lowered CSF PrP concentration in prion disease is a genuine result of the disease process and not an artifact of ELISA-based measurement. As a result, dose-finding studies for PrP lowering drugs may need to be conducted in presymptomatic at-risk individuals rather than in symptomatic patients. We provide a targeted mass spectrometry-based method suitable for preclinical quantification of CSF PrP as a tool for drug development.

Use of the Air Force Post-Deployment Health Reassessment for the identification of depression and posttraumatic stress disorder: public health implications for suicide prevention.

OBJECTIVES: Military members are required to complete the Post-Deployment Health Assessment on return from deployment and the Post-Deployment Health Reassessment (PHDRA) 90 to 180 days later, and we assessed the PDHRA's sensitivity and specificity in identifying posttraumatic stress disorder (PTSD) and depression after a military deployment among US Air Force personnel. METHODS: We computed the PDHRA's sensitivity and specificity for depression and PTSD and developed a structural model to suggest possible improvements to it. RESULTS: For depression, sensitivity and specificity were 0.704 and 0.651, respectively; for PTSD, they were 0.774 and 0.650, respectively. Several variables produced significant direct effects on depression and trauma, suggesting that modifications could increase its sensitivity and specificity. CONCLUSIONS: The PDHRA was moderately effective in identifying airmen with depression and PTSD. It identified behavioral health concerns in many airmen who did not develop a diagnostic mental health condition. Its low level of specificity may result in reduced barriers to care and increased support services, key components of a public health approach to suicide prevention, for airmen experiencing subacute levels of distress after deployment, which may, in part, account for lower suicide rates among airmen after deployment.

Mood, anxiety, and substance-use disorders and suicide risk in a military population cohort.

There are meager prospective data from nonclinical samples on the link between anxiety disorders and suicide or the extent to which the association varies over time. We examined these issues in a cohort of 309,861 U.S. Air Force service members, with 227 suicides over follow-up. Mental disorder diagnoses including anxiety, mood, and substance-use disorders (SUD) were based on treatment encounters. Risk for suicide associated with anxiety disorders were lower compared with mood disorders and similar to SUD. Moreover, the associations between mood and anxiety disorders with suicide were greatest within a year of treatment presentation.