Minimally invasive biomarker confirms glial activation present in Alzheimer's disease: a preliminary study

Abstract

We applied (13)C magnetic resonance spectroscopy (MRS), a nonradioactive, noninvasive brain imaging technique, to quantify the oxidation of [1-(13)C] acetate in a conventional clinical magnetic resonance imaging (MRI) scanner in five consecutive elderly subjects at various clinical stages of Alzheimer's disease (AD) progression. [1-(13)C] acetate entered the brain and was metabolized to [5-(13)C] glutamate and glutamine, as well as [1-(13)C] glutamate and glutamine, and the final glial oxidation product, (13)C bicarbonate, at a linear rate. Calculation of the initial slope was similar in a single subject, examined twice, 1 month apart (test-re-test 8%). Mean rate of cerebral bicarbonate production in this elderly group was 0.040 ± 0.01 (n = 5). Assuming that the rate of conversion of acetate to bicarbonate is a reflection of glial metabolic rate and that glial metabolic rate is a surrogate marker for 'neuroinflammation', our preliminary results suggest that [1-(13)C] MRS may provide biomarkers for diseases, believed to involve microglia and other cells of the astrocyte series. Among these is AD, for which novel drugs which ameliorate the damaging effects of neuroinflammation before symptoms of dementia appear, are in advanced development. The value of (13)C MRS as an early, noninvasive biomarker may lie in the conduct of cost-effective clinical trials.

Keywords: Alzheimer’s disease; glial activation; noninvasive biomarker.

Figure 1

Proton MRS spectra from healthy elderly (A), an elderly subject with MCI (B) and an AD patient (C). Spectra were scaled to creatine peak intensity. Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment; mI, myo-inositol; MRS, magnetic resonance spectroscopy; NAA, N-acetyl aspartate.

Figure 2

Typical spectra (147–167 ppm region) of ¹³C MRS in an AD subject at baseline (A) and at 1 hour after start of infusion (B). Abbreviations: MRS, magnetic resonance spectroscopy; AD, Alzheimer’s disease; tCr, total creatine.

Figure 3

Significant correlation of the rate of bicarbonate productions in % fractional enrichment (FE) of bicarbonate per minute and the clinical measure, mini-mental state examination (MMSE) with R² = 0.908 (A) and glial cell density from proton MRS (mI/Cr) with R² = 0.753 (B). Abbreviations: AD, Alzheimer’s disease; Cr, creatine; FE, fractional enrichment; mI, myo-inositol; MCI, mild cognitive impairment; MRS, magnetic resonance spectroscopy; MMSE, mini-mental state examination.