Randomized Trial of Marine n-3 Polyunsaturated Fatty Acids for the Prevention of Cerebral Small Vessel Disease and Inflammation in Aging (PUFA Trial): Rationale, Design and Baseline Results

Abstract

Vascular risk factors for age-related cognitive decline are significant, and their management may ultimately prove the most successful strategy for reducing risk and sustaining cognitive health. This randomized, double-blinded, placebo-controlled trial with parallel group allocation to either marine n-3 polyunsaturated fatty acids (n-3 PUFA) or soybean oil placebo assesses the effects on the total volume of accumulation in cerebral white matter hyperintensities (WMH), a potentially modifiable neurovascular component of age-related cognitive decline. Total WMH accumulation over 3 years is the primary endpoint. The safety and efficacy of n-3 PUFA is evaluated in older adults with significant WMH and suboptimum plasma n-3 PUFA as inclusion criteria. One hundred and two non-demented older adults were enrolled with a mean age of 81.1 (±4.4) years, WMH of 19.4 (±16.1) cm³, and a plasma n-3 PUFA of 86.64 (±29.21) µg/mL. 61% were female, 28% were apolipoprotein E epsilon 4 carriers, and the mean mini-mental state exam (MMSE) was 27.9 (±1.7). This trial provides an initial evaluation of n-3 PUFA effects on WMH, a reproducible and valid risk biomarker for cognitive decline, as well as on inflammatory biomarkers thought to play a role in WMH accumulation. We present the baseline results and operational experience of enriching a study population on advanced age, blood n-3 PUFA, and magnetic resonance imaging (MRI) derived WMH with biomarker outcomes (WMH, inflammation markers) in a dementia prevention paradigm.

Keywords: MRI; cognitive decline; docosahexaenoic acid; eicosapentaenoic acid; elderly; executive function; neuroimaging; vascular cognitive impairment; white matter hyperintensities.

Figure 1

Hypothetical model for n-3 PUFA effects on age-related cognitive decline. Administration of n-3 PUFA makes them available for incorporation into cellular membranes and subsequent release by intracellular phospholipases that convert them into a variety of lipid bioactives. Unesterified circulating n-3 PUFA can arrive at sites of inflammation and undergo conversion into specialized pro-resolving lipid mediators, including the E-series resolvins derived from EPA via p450 metabolism, or aspirin acetylated cyclooxygenase and the D series resolvins, protectins, and maresins, derived from DHA via lipoxygenase or aspirin acetylated COX-2 [49]. Administration of n-3 PUFA is associated with down-regulation of cell adhesion molecules [48] that may govern blood–brain barrier permeability in older adults [31]. These cell adhesion molecules may play a role in cerebral small vessel disease as reflected by the accumulation magnetic resonance imaging derived white matter hyperintensities. Executive function and speed of processing are domains of cognition impacted by the accumulation of WMH, in contrast to episodic memory recall more influenced by deposits of Alzheimer pathology.

Figure 2

Neuroimaging endpoints available in the PUFA Trial. (A). Fluid-attenuated inversion recovery (FLAIR) sequence illustrating prominent total WMH; (B). WMH segmentation classified into deep (green) and periventricular (blue); (C). T1 grey matter segmentation including medial temporal lobe (brown); (D). 2D Pseudo-Continuous Arterial Spin Labeling (pCASL) sequence for cerebral blood flow; (E). Diffusion Tensor Imaging (DTI) derived fractional anisotropy direction color-coded; (F). fMRI derived default mode network activity at resting state.

Figure 3

PUFA Trial Participant Flow.