Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer's disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist

Am J Psychiatry. 1997 Oct;154(10):1459-61. doi: 10.1176/ajp.154.10.1459.


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.

Method: 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.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / biosynthesis
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism*
  • Brain / metabolism*
  • Choline / metabolism
  • Creatine / metabolism
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Frontal Lobe / metabolism
  • Glycerylphosphorylcholine / administration & dosage
  • Glycerylphosphorylcholine / metabolism
  • Humans
  • Magnetic Resonance Spectroscopy*
  • Muscarinic Antagonists / administration & dosage
  • Muscarinic Antagonists / therapeutic use*
  • Neurons / metabolism
  • Parasympathetic Nervous System / metabolism
  • Protons
  • Pyridines / therapeutic use*
  • Thiadiazoles / therapeutic use*


  • Muscarinic Antagonists
  • Protons
  • Pyridines
  • Thiadiazoles
  • Glycerylphosphorylcholine
  • xanomeline
  • Creatine
  • Choline
  • Acetylcholine