Plasma signature of neurological disease in the monogenetic disorder Niemann Pick Type C [Molecular Bases of Disease]

January 31st, 2014 by Alam, M. S., Getz, M., Yi, S., Kurkewich, J., Safeukui, I., Haldar, K.

Early diagnosis of neurological disorders would greatly improve their management and treatment. A major hurdle is that inflammatory products of cerebral disease are not easily detected in blood. Inflammation in multiple organs and heterogeneity in disease present additional challenges in distinguishing the extent to which a blood based marker reflects disease in brain or other afflicted organs. Murine models of the monogenetic disorder Niemann Pick Type C (NPC) present aggressive forms of cerebral and liver inflammatory disease. Microarray analyses previously revealed age-dependent changes in innate immunity transcripts in the mouse brain. We have now validated four putative secretory inflammatory markers that are also elevated in mouse liver. We include limited, but first time analysis of human NPC liver and cerebellum. Further we utilized 2-hydroxypropyl-beta-cyclodextrin (HPβCD; an emerging therapeutic) administered intraperitoneally in mice, which abrogates inflammatory pathology in the liver but has limited effect on the brain. By analyzing the corresponding effects on inflammatory plasma proteins, we identified cathepsin S as a lead indicator of liver disease. In contrast lysozyme was a marker of both brain and liver disease. HPβCD had no effect on transcripts of neuron specific 24-hydroxylase and its product 24(S)-hydroxycholesterol was not a useful indicator in mouse plasma. Our data suggest that dual analysis of levels of the inflammatory markers lysozyme and cathepsin S may enable detection of multiple distinct states of neurodegeneration in plasma.