What have novel imaging techniques revealed about metabolism in the aging brain?

Abstract

Brain metabolism declines with age and do so in an accelerated manner in neurodegenerative disorders. Noninvasive neuroimaging techniques have played an important role to identify the metabolic biomarkers in aging brain. Particularly, PET with fluorine-18 (¹⁸F)-labeled 2-fluoro-2-deoxy-d-glucose tracer and proton magnetic resonance spectroscopy (MRS) have been widely used to monitor changes in brain metabolism over time, identify the risk for Alzheimer's disease (AD) and predict the conversion from mild cognitive impairment to AD. Novel techniques, including PET carbon-11 Pittsburgh compound B, carbon-13 and phosphorus-31 MRS, have also been introduced to determine Aβ plaques deposition, mitochondrial functions and brain bioenergetics in aging brain and neurodegenerative disorders. Here, we introduce the basic principle of the imaging techniques, review the findings from 2-fluoro-2-deoxy-d-glucose-PET, Pittsburgh compound B PET, proton, carbon-13 and phosphorus-31 MRS on changes in metabolism in normal aging brain, mild cognitive impairment and AD, and discuss the potential of neuroimaging to identify effective interventions and treatment efficacy for neurodegenerative disorders.

Keywords: APOE4; Alzheimer’s disease; Aβ plaques; PET; aging; glucose metabolism; magnetic resonance spectroscopy; mild cognitive impairment; mitochondrial function.

Figure 1. Fluorine-18-labeled 2-fluoro-2-deoxy-d-glucose-PET and Pittsburgh compound B PET in Alzheimer’s disease and normal control individuals

Compared with the controls, FDG (represents brain glucose metabolism) dramatically reduced, while PIB (represents Aβ deposition) significantly increased in AD patients. AD: Alzheimer’s disease; FDG: Fluorine-18-labeled 2-fluoro-2-deoxy-d-glucose; PIB: Pittsburgh compound B. Reproduced with permission from [13].

Figure 2. ¹H magnetic resonance spectroscopy study design and spectrum

(A) A mid-sagittal MRI view of the voxel placement for MRS experiments. (B) A representative spectrum of proton MRS. Cho: Choline; Cr: Creatine; Glx: Glutamate and glutamine; mI: Myo-Inositol; MRS: Magnetic resonance spectroscopy; NAA: N-acetyl aspartate; ppm: Parts per million.

Figure 3. The glutamate/glutamine cycle and ¹³C spectra

(A) The diagram shows the metabolic pathways within glutamatergic neurons and surrounding astroglial cells. Glucose and lactate enter both the glial (V_TCAa) and neuronal (V_TCAn) TCA cycles via pyruvate dehydrogenase (V_PDH), β-HB is directly incorporated into the neuronal and astroglial TCA cycles, and acetate is near-exclusively incorporated into the glial TCA cycle. Neuronal Glu that is released via neurotransmission is taken up by astroglial cells and converted by Gln synthetase to Gln at a rate proportional to the Glu/Gln cycle. The synthesis of Gln is believed to be exclusively within astroglia and other glial cells. In addition to neurotransmitter cycling, Gln may be synthesized de novo starting with the pyruvate carboxylase reaction (V_PC). Gln synthesized via pyruvate carboxylase can replace neurotransmitter Glu oxidized in the astrocyte or elsewhere (and be recycled back to the neuron) or leave the brain (V_efflux) to remove ammonia and maintain the nitrogen balance. To measure the rates of these pathways, ¹³C-labeled substrates are used and the flow of ¹³C isotope into Glu and Gln is measured using ¹³C MRS. For detailed descriptions of how these pathways are tracked using ¹³C-MRS, and how isotopically labeled substrates and rates are calculated by metabolic modeling, see [16,17]. (B) A ¹³C spectrum with of [1⁻¹³C] glucose infusion. α-KG: α-ketoglutarate; β-HB: β-hydroxybutyrate; AcCoA: Acetyl-CoA; Asp: Aspartate; Gln: Glutamine; Glu: Glutamate; Glut1: Glucose transporter 1; Lac: Lactate; MCT1: Monocarboxylate transporter 1; OAA: Oxaloacetate; ppm: Parts per million; Pyr: Pyruvate; TCA: Tricarboxylic acid; V_efflux: Efflux rate; V_TCAα: Tricarboxylic acid flux rate of astrocytes; V_TCAn: Tricarboxylic acid flux rate of neurons. Reproduced with permission from [18].

Figure 4. Representative surface-coil localized in vivo ³¹P magnetic resonance spectra of normal cat brains at 16.4 T

Full spectrum is shown at the bottom. Enlarged spectral region (chemical shift from −9 to −11.5 ppm) with phase and baseline correction is shown in the bottom inset (gray lines), superimposed by the model predicted spectrum (red line). The model decomposed individual signals of NAD⁺ (black line), NADH (green line) and α-ATP (blue line) are shown in the middle inset, and the residue of model fittings to the original ³¹P spectra is plotted in the top of inset. PCr: Phosphocreatine; PDE: Phosphodiester; Pi: Inorganic phosphate; PME: Phosphomonoester; ppm: Parts per million. Reproduced with permission from [26].