MICEST: A potential tool for non-invasive detection of molecular changes in Alzheimer's disease

Myo-inositol (mIns) is a marker of glial cells proliferation and has been shown to increase in early Alzheimer's disease (AD) pathology. mIns exhibits a concentration dependent chemical-exchange-saturation-transfer (CEST) effect (MICEST) between its hydroxyl groups and bulk water protons. Using the endogenous MICEST technique brain mIns concentration and glial cells proliferation can be mapped at high spatial resolution. The high resolution mapping of mIns was performed using MICEST technique on ∼20 months old APP-PS1 transgenic mouse model of AD as well as on age matched wild type (WT) control (n=5). The APP-PS1 mice show ∼50% higher MICEST contrast than WT control with concomitant increase in mIns concentration as measured through proton spectroscopy. Immunostaining against glial-fibric-acidic protein also depicts proliferative glial cells in larger extent in APP-PS1 than WT mice, which correspond to the higher mIns concentration. Potential significance of MICEST in early detection of AD pathology is discussed in detail.

[1]  R. Mrak,et al.  Microglia and neuroinflammation: a pathological perspective , 2004 .

[2]  A Dean Sherry,et al.  Chemical exchange saturation transfer contrast agents for magnetic resonance imaging. , 2008, Annual review of biomedical engineering.

[3]  G. E. Alexander,et al.  Brain metabolite concentration and dementia severity in Alzheimer’s disease , 2001, Neurology.

[4]  Kejia Cai,et al.  Targeted PARACEST nanoparticle contrast agent for the detection of fibrin , 2006, Magnetic resonance in medicine.

[5]  R S Balaban,et al.  Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST) , 2000, Magnetic resonance in medicine.

[6]  J. Trojanowski,et al.  Neurodegenerative tauopathies. , 2001, Annual review of neuroscience.

[7]  Gil Navon,et al.  Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST) , 2008, Proceedings of the National Academy of Sciences.

[8]  J. Wegiel,et al.  Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease , 2004, Neurobiology of Aging.

[9]  R. von Bernhardi Glial cell dysregulation: a new perspective on Alzheimer disease. , 2007, Neurotoxicity research.

[10]  Jinyuan Zhou,et al.  Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI , 2003, Nature Medicine.

[11]  M. Aschner,et al.  Glial cells in neurotoxicity development. , 1999, Annual review of pharmacology and toxicology.

[12]  F. Zang,et al.  Role of Myo-Inositol by Magnetic Resonance Spectroscopy in Early Diagnosis of Alzheimer’s Disease in APP/PS1 Transgenic Mice , 2010, Dementia and Geriatric Cognitive Disorders.

[13]  Roger N Gunn,et al.  In-vivo measurement of activated microglia in dementia , 2001, The Lancet.

[14]  Shih-Yi Lin,et al.  Glial activation involvement in neuronal death by Japanese encephalitis virus infection. , 2010, The Journal of general virology.

[15]  C. Jack,et al.  Proton MR spectroscopy in mild cognitive impairment and Alzheimer disease: comparison of 1.5 and 3 T. , 2003, AJNR. American journal of neuroradiology.

[16]  A. Smith,et al.  Comparison of Pathological Diagnostic Criteria for Alzheimer Disease , 1998, Alzheimer disease and associated disorders.

[17]  Xavier Golay,et al.  Amide proton transfer imaging of human brain tumors at 3T , 2006, Magnetic resonance in medicine.

[18]  T. Guilarte,et al.  Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS , 2005, Journal of NeuroVirology.

[19]  Clifford R Jack,et al.  Monitoring disease progression in transgenic mouse models of Alzheimer's disease with proton magnetic resonance spectroscopy. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R S Balaban,et al.  A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). , 2000, Journal of magnetic resonance.

[21]  Peter C M van Zijl,et al.  MRI detection of glycogen in vivo by using chemical exchange saturation transfer imaging (glycoCEST) , 2007, Proceedings of the National Academy of Sciences.

[22]  N. Schuff,et al.  Regional Myo-inositol Concentration in Mild Cognitive Impairment Using 1H Magnetic Resonance Spectroscopic Imaging , 2009, Alzheimer disease and associated disorders.

[23]  R. Coleman,et al.  Neuroimaging and early diagnosis of Alzheimer disease: a look to the future. , 2003, Radiology.

[24]  A Gregory Sorensen,et al.  Correction for artifacts induced by B0 and B1 field inhomogeneities in pH‐sensitive chemical exchange saturation transfer (CEST) imaging , 2007, Magnetic resonance in medicine.

[25]  Ravinder Reddy,et al.  In vivo mapping of brain myo-inositol , 2011, NeuroImage.