In vivo 1H-magnetic resonance spectroscopy can detect metabolic changes in APP/PS1 mice after donepezil treatment

BackgroundDonepezil improves cognitive functions in AD patients. Effects on the brain metabolites N-acetyl-L-aspartate, choline and myo- inositol levels have been reported in clinical studies using this drug. The APP/PS1 mouse coexpresses the mutated forms of human β-amyloid precursor protein (APP) and mutated human presenilin 1 (PS1). Consequently, the APP/PS1 mouse model reflects important features of the neurochemical profile in humans. In vivo magnetic resonance spectroscopy (1H-MRS) was performed in fronto-parietal cortex and hippocampus (ctx/hipp) and in striatum (str). Metabolites were quantified using the LCModel and the final analysis was done using multivariate data analysis. The aim of this study was to investigate if multivariate data analysis could detect changes in the pattern of the metabolic profile after donepezil treatment.ResultsSignificant differences were observed in the metabolic pattern of APP/PS1 mice in both str and ctx/hipp before and after donepezil treatment using multivariate data analysis, evidencing a significant treatment effect. A treatment effect was also seen in wild type (wt) mice in str. A significant decrease in the metabolic ratio taurine/creatine (Tau/tCr) was related to donepezil treatment (p < 0.05) in APP/PS1 mice in both brain regions. Furthermore, a significant influence on the choline/creatine (tCho/tCr) level was observed in treated APP/PS1 mice compared to untreated in str (p = 0.011). Finally, there was an increase in glutamate/creatine (Glu/tCr) in str in wt mice treated with donepezil.ConclusionMultivariate data analysis can detect changes in the metabolic profile in APP/PS1 mice after donepezil treatment. Effects on several metabolites that are measurable in vivo using MR spectroscopy were observed. Changes in Tau/tCr and tCho/tCr could possibly be related to changed cholinergic activity caused by donepezil treatment.

[1]  G. Higgins,et al.  Transgenic mouse models of Alzheimer's disease: phenotype and application , 2003, Behavioural pharmacology.

[2]  R. Gruetter,et al.  In vivo magnetic resonance spectroscopy of human brain: the biophysical basis of dementia. , 1997, Biophysical chemistry.

[3]  Kefei Chen,et al.  Behavioral phenotypes of amyloid‐based genetically modified mouse models of Alzheimer's disease , 2005, Genes, brain, and behavior.

[4]  P. D. De Deyn,et al.  Drug discovery in dementia: the role of rodent models. , 2006, Nature reviews. Drug discovery.

[5]  B. Seltzer.  Donepezil: a review , 2005, Expert opinion on drug metabolism & toxicology.

[6]  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.

[7]  P. Layer,et al.  Mouse acetylcholinesterase interacts in yeast with the extracellular matrix component laminin‐1β , 2004, FEBS letters.

[8]  J. Rybakowski,et al.  One‐year treatment of Alzheimer's disease with acetylcholinesterase inhibitors: improvement on ADAS‐cog and TMT A, no change or worsening on other tests , 2005, Human psychopharmacology.

[9]  Xin Yu,et al.  Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer's disease. , 2003, The American journal of psychiatry.

[10]  J Hennig,et al.  RARE imaging: A fast imaging method for clinical MR , 1986, Magnetic resonance in medicine.

[11]  J. Hardy,et al.  Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP , 2001, Science.

[12]  T. Hasegawa,et al.  Effects of metrifonate on memory impairment and cholinergic dysfunction in rats. , 1997, European journal of pharmacology.

[13]  Ulf Norinder,et al.  Age related changes in brain metabolites observed by 1H MRS in APP/PS1 mice , 2008, Neurobiology of Aging.

[14]  J. Hardy,et al.  Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1 , 1996, Nature.

[15]  Bengt Winblad,et al.  Of mice and men: more neurobiology in dementia , 2006, Current opinion in psychiatry.

[16]  D. Auer,et al.  Hippocampal metabolic abnormalities in mild cognitive impairment and Alzheimer's disease , 2005, Neuroscience Letters.

[17]  R. Bartha,et al.  High field 1H MRS of the hippocampus after donepezil treatment in Alzheimer disease , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[18]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[19]  K. Courtney,et al.  A new and rapid colorimetric determination of acetylcholinesterase activity. , 1961, Biochemical pharmacology.

[20]  K. Kendrick,et al.  Effects of ENA713 and CHF2819, two anti-Alzheimer’s disease drugs, on rat amino acid levels , 2001, Brain Research.

[21]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[22]  Napapon Sailasuta,et al.  A comparative study of myo-inositol quantification using LCmodel at 1.5 T and 3.0 T with 3 D 1H proton spectroscopic imaging of the human brain. , 2004, Magnetic resonance imaging.

[23]  K. Kuriyama,et al.  A modulating role of taurine on release of acetylcholine and norepinephrine from neuronal tissues. , 1978, Japanese journal of pharmacology.

[24]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[25]  Manuel Buttini,et al.  Mice as models: transgenic approaches and Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[26]  R. Gruetter,et al.  In vivo 1H NMR spectroscopy of rat brain at 1 ms echo time , 1999, Magnetic resonance in medicine.

[27]  H. Haas,et al.  Long‐lasting enhancement of corticostriatal neurotransmission by taurine , 2002, The European journal of neuroscience.

[28]  M. Law,et al.  Magnetic resonance spectroscopy of the brain: review of metabolites and clinical applications. , 2009, Clinical radiology.

[29]  J. O'Brien,et al.  A Comprehensive Review of Proton Magnetic Resonance Spectroscopy Studies in Dementia and Parkinson’s Disease , 2002, Dementia and Geriatric Cognitive Disorders.

[30]  S. Provencher.  Estimation of metabolite concentrations from localized in vivo proton NMR spectra , 1993, Magnetic resonance in medicine.

[31]  D. Borchelt,et al.  Accelerated Amyloid Deposition in the Brains of Transgenic Mice Coexpressing Mutant Presenilin 1 and Amyloid Precursor Proteins , 1997, Neuron.

[32]  A Hofman,et al.  MR spectroscopy of brain white matter in the prediction of dementia , 2006, Neurology.

[33]  E G Tangalos,et al.  Regional metabolic patterns in mild cognitive impairment and Alzheimer’s disease , 2000, Neurology.

[34]  E G Tangalos,et al.  1H MR spectroscopy in common dementias , 2004, Neurology.

[35]  Ji-Kyung Choi,et al.  Magnetic resonance spectroscopic analysis of Alzheimer's disease mouse brain that express mutant human APP shows altered neurochemical profile , 2004, Brain Research.

[36]  Eric Westman,et al.  Carbamazepine treatment recovered low N-acetylaspartate+N-acetylaspartylglutamate (tNAA) levels in the megencephaly mouse BALB/cByJ-Kv1.1 mceph/mceph , 2007, Neurobiology of Disease.

[37]  F. Jessen,et al.  Treatment monitoring and response prediction with proton MR spectroscopy in AD , 2006, Neurology.

[38]  K. Kantarci.  1H magnetic resonance spectroscopy in dementia. , 2007, The British journal of radiology.

[39]  J. Hardy,et al.  Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes , 1998, Nature Medicine.

[40]  L. Mucke,et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein , 1995, Nature.

[41]  M N Rossor,et al.  MRS shows abnormalities before symptoms in familial Alzheimer disease , 2006, Neurology.

[42]  S. Provencher.  Automatic quantitation of localized in vivo 1H spectra with LCModel , 2001, NMR in biomedicine.