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


RESULTS
Significant 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.


CONCLUSIONS
Multivariate 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.
Department of Neurobiology, Health Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. eric.westman@ki.se
Eric
E
Westman
Christian
C
Spenger
Johanna
J
Oberg
Henry
H
Reyer
Jens
J
Pahnke
Lars-Olof
LO
Wahlund
D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002794:Choline / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D000077265:Donepezil; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015999:Multivariate Analysis; D009154:Mutation; D010296:Parietal Lobe / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D013654:Taurine / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D007189:Indans; C508853:PSEN1 protein, human; D010880:Piperidines; D053764:Presenilin-1; D013654:Taurine; D018698:Glutamic Acid; D000077265:Donepezil; D003401:Creatine; D002794:Choline