Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer's disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist.
OBJECTIVE
Higher than normal cellular levels of the phospholipid catabolic intermediate glycerophosphocholine have been found in postmortem brain tissue of persons with Alzheimer's disease. Proton magnetic resonance spectroscopy (1H-MRS) can detect a choline resonance that is largely due to glycerophosphocholine. The authors tested the hypothesis that treatment with xanomeline, an M1 selective muscarinic cholinergic agonist, would be associated with a decrease in the 1H-MRS choline resonance.


METHODS
Patients with mild to moderate Alzheimer's disease received placebo or xanomeline for 6 months. 1H-MRS spectra were collected at baseline and after treatment discontinuation for 12 patients, two taking placebo and 10 taking xanomeline at a dose of 25 mg t.i.d. (N = 4), 50 mg t.i.d. (N = 3), or 75 mg t.i.d. (N = 3).


RESULTS
For the combined group of patients taking xanomeline, there was a significant decrease in the choline/creatine ratio from baseline to endpoint.


CONCLUSIONS
Treatment of Alzheimer's disease with a cholinergic agonist is associated with a decrease in the MRS choline resonance. Xanomeline may reduce breakdown of cholinergic neuron membranes by reducing the cellular requirement for free choline for acetylcholine synthesis.
Satlin
A
A
Department of Psychiatry, McLean Hospital, Belmont, MA 02178, USA. asatlin@warren.med.harvard.edu
Bodick
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N
Offen
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Renshaw
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PF
D000109:Acetylcholine / Q000096:biosynthesis; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002794:Choline / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005625:Frontal Lobe / Q000378:metabolism; D005997:Glycerylphosphorylcholine / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D009474:Neurons / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000378:metabolism; D011522:Protons; D011725:Pyridines / Q000627:therapeutic use*; D013830:Thiadiazoles / Q000627:therapeutic use*
D018727:Muscarinic Antagonists; D011522:Protons; D011725:Pyridines; D013830:Thiadiazoles; D005997:Glycerylphosphorylcholine; C075257:xanomeline; D003401:Creatine; D002794:Choline; D000109:Acetylcholine