Kinetics of neurodegeneration based on a risk-related biomarker in animal model of glaucoma

Molecular Neurodegeneration

Hirotaka Onoe²  Hideaki Hara⁷  Yasuyoshi Watanabe⁴  Shin-ichi Urayama⁵  Hajime Yamanaka¹  Yasushi Ito⁷  Yuta Inokuchi⁷  Takayuki Ose⁶  Hiroshi Watabe³  Masamitsu Shimazawa⁷  Takuya Hayashi² 

[1] Functional Probe Research Laboratory, RIKEN Center for Molecular Imaging Science, Kobe, Hyogo, 650-0047, Japan;Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, 545-8586, Japan;Faculty of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan;Molecular Probe Dynamics Laboratory, RIKEN Center for Molecular Imaging Science, Kobe, Hyogo, 650-0047, Japan;Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan;Department of Investigative Radiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, 565-8565, Japan;Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, 501-1196, Japan

关键词: Glaucoma;    Kinetic model;    Biomarker;    Neurodegenerative mechanisms;    Diffusion tensor;   

Others  :  863284
DOI  :  10.1186/1750-1326-8-4

 received in 2012-05-18, accepted in 2013-01-04,  发布年份 2013

【 摘 要 】

Background

Neurodegenerative diseases including Parkinson’s and Alzheimer’s diseases progress slowly and steadily over years or decades. They show significant between-subject variation in progress and clinical symptoms, which makes it difficult to predict the course of long-term disease progression with or without treatments. Recent technical advances in biomarkers have facilitated earlier, preclinical diagnoses of neurodegeneration by measuring or imaging molecules linked to pathogenesis. However, there is no established “biomarker model” by which one can quantitatively predict the progress of neurodegeneration. Here, we show predictability of a model with risk-based kinetics of neurodegeneration, whereby neurodegeneration proceeds as probabilistic events depending on the risk.

Results

We used five experimental glaucomatous animals, known for causality between the increased intraocular pressure (IOP) and neurodegeneration of visual pathways, and repeatedly measured IOP as well as white matter integrity by diffusion tensor imaging (DTI) as a biomarker of axonal degeneration. The IOP in the glaucomatous eye was significantly increased than in normal and was varied across time and animals; thus we tested whether this measurement is useful to predict kinetics of the integrity. Among four kinds of models of neurodegeneration, constant-rate, constant-risk, variable-risk and heterogeneity models, goodness of fit of the model and F-test for model selection showed that the time course of optic nerve integrity was best explained by the variable-risk model, wherein neurodegeneration kinetics is expressed in an exponential function across cumulative risk based on measured IOP. The heterogeneity model with stretched exponential decay function also fit well to the data, but without statistical superiority to the variable-risk model. The variable-risk model also predicted the number of viable axons in the optic nerve, as assessed by immunohistochemistry, which was also confirmed to be correlated with the pre-mortem integrity of the optic nerve. In addition, the variable-risk model identified the disintegrity in the higher-order visual pathways, known to underlie the transsynaptic degeneration in this disease.

Conclusions

These findings indicate that the variable-risk model, using a risk-related biomarker, could predict the spatiotemporal progression of neurodegeneration. This model, virtually equivalent to survival analysis, may allow us to estimate possible effect of neuroprotection in delaying progress of neurodegeneration.

【 授权许可】

   
2013 Hayashi et al; licensee BioMed Central Ltd.

【 图 表 】

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