Docosahexaenoic acid (DHA) incorporation into the brain from plasma, as an in vivo biomarker of brain DHA metabolism and neurotransmission

Abstract

Docosahexaenoic acid (DHA) is critical for maintaining normal brain structure and function, and is considered neuroprotective. Its brain concentration depends on dietary DHA content and hepatic conversion from its dietary derived n-3 precursor, α-linolenic acid (α-LNA). We have developed an in vivo method in rats using quantitative autoradiography and intravenously injected radiolabeled DHA to image net incorporation into the brain of unesterified plasma DHA, and showed with this method that the incorporation rate of DHA equals the rate of brain metabolic DHA consumption. The method has been extended for use in humans with positron emission tomography (PET). Furthermore, imaging in unanesthetized rats using DHA incorporation as a biomarker in response to acute N-methyl-D-aspartate administration confirms that regional DHA signaling is independent of extracellular calcium, and likely mediated by a calcium-independent phospholipase A(2) (iPLA(2)). Studies in mice in which iPLA(2)-VIA (β) was knocked out confirmed that this enzyme is critical for baseline and muscarinic cholinergic signaling involving DHA. Thus, quantitative imaging of DHA incorporation from plasma into brain can be used as an in vivo biomarker of brain DHA metabolism and neurotransmission.

Figure 1

Daily DHA consumption rate by human brain. Measurements were performed by injecting [1-¹¹C]DHA intravenously in volunteers and using positron emission tomography [28].

Figure 2

NMDA (25 mg/kg i.p.) initiates arachidonic but not docosahexaenoic acid signaling in rat brain. Coronal autoradiographs of brains from rat injected with NMDA compared to animals injected with saline. FR, frontal cortex; CPU, caudate-putamen, DB, diagonal band; Mot, motor cortex; Hipp, hippocampus. Incorporation coefficients k* are color-coded. From [41].