Non-Invasive Imaging of the Cholinergic System – Distribution and Function

Lay Summary

MRS Imaging Signal Enhancement May Aid Alzheimer’s Diagnosis and Treatment Monitoring

By strengthening the signal produced by MRS imaging, the researchers will test in animals a potential new non-invasive imaging technique for diagnosing dementia and monitoring treatment effectiveness.

Most treatments designed to delay the onset of dementia currently attempt to inhibit the breakdown of the brain chemical acetylcholine, a neurotransmitter used by neurons involved in cognition and memory. These cholinergic neurons severely degenerate in patients with dementia. The researchers have used carbon-13 Magnetic Resonance Spectroscopy (¹³C-MRS) to follow the rate of synthesis of acetylcholine from the brain chemical choline, in live laboratory brain tissue cultures. The rate is a direct measure, a biomarker, for the functioning of cholinergic neurons in the brain.

Now they plan to induce more than 10,000 fold increase in ¹³C-MRS sensitivity, sharpening its temporal and spatial resolution, by hyperpolarizing choline in the laboratory and administering it to laboratory animals prior to ¹³C-MRSimaging. If this enhanced imaging technique is effective in laboratory animals, the researchers would seek funding from other sources to initiate testing in humans with mild cognitive impairment and those with dementia to determine whether this non-invasive imaging tool can effectively diagnose dementia and monitor effects of treatments designed to inhibit acetylcholine breakdown.

Significance:  This ¹³C-MRSimaging enhancement may eventually prove to be a safe and effective non-invasive tool for diagnosing dementia in humans and assessing experimental therapies.

Abstract

Non-Invasive Imaging of the Cholinergic System - Distribution and Function

Choline is a nutrient that serves as an essential precursor for acetylcholine synthesis. Cholinergic neurons (defined by their ability to synthesize acetylcholine from choline) in the basal forebrain nuclei are known to severely degenerate in demented aged and Alzheimer's disease patients. We have previously demonstrated the ability to follow, in real time, the rate of conversion of choline to acetylcholine in live brain slices by carbon-13 Magnetic Resonance Spectroscopy (¹³C-MRS). This rate is a direct measure of cholinergic activity and is a marker for the function of cholinergic neurons in the brain. In this proposed research we aim to develop this methodology further to enable direct and non-invasive monitoring of the cholinergic function in the human brain.

The sensitivity of the method will be dramatically increased using a novel sensitivity enhancement technique for ¹³C-MRS, namely, parahydrogen induced polarization (PHIP), or hyperpolarization. This technique enables an increase of five orders of magnitude in the ¹³C signal on magnetic resonance examinations, which will be utilized to increase the temporal and the spatial resolution of cholinergic imaging. We expect that using this methodology, visualization of acetylcholine synthesis will be made possible at very high a temporal resolution (< 1 second) and spatial resolution (< 5 mm). We expect that these studies will provide a new, safe, non-invasive, and accurate tool for cholinergic system characterization, thus improving the ability to diagnose and monitor treatment in patients with mild cognitive impairment, AD, and dementia of various forms.