Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging

Abstract

Leading a mentally stimulating life may build up a reserve of neural and mental resources that preserve cognitive abilities in late life. Recent autopsy evidence links neuronal density in the locus coeruleus (LC), the brain's main source of norepinephrine, to slower cognitive decline before death, inspiring the idea that the noradrenergic system is a key component of reserve (Robertson, I. H. 2013. A noradrenergic theory of cognitive reserve: implications for Alzheimer's disease. Neurobiol. Aging. 34, 298-308). Here, we tested this hypothesis using neuromelanin-sensitive magnetic resonance imaging to visualize and measure LC signal intensity in healthy younger and older adults. Established proxies of reserve, including education, occupational attainment, and verbal intelligence, were linearly correlated with LC signal intensity in both age groups. Results indicated that LC signal intensity was significantly higher in older than younger adults and significantly lower in women than in men. Consistent with the LC-reserve hypothesis, both verbal intelligence and a composite reserve score were positively associated with LC signal intensity in older adults. LC signal intensity was also more strongly associated with attentional shifting ability in older adults with lower cognitive reserve. Together these findings link in vivo estimates of LC neuromelanin signal intensity to cognitive reserve in normal aging.

Keywords: Aging; Brain reserve; Cognitive reserve; Gender; Locus coeruleus; Norepinephrine; Sex.

Fig. 1

Locus coeruleus (LC) anatomic tracing protocol. Step 1: in the axial plane, the inferiormost slice of the inferior colliculus (IC) was located; we then moved down 7 mm (2 slices) into a slice where LC signal intensities were most apparent. Step 2: left and right LC regions of interest (ROIs) appeared as high (bright) signal intensities neighboring the corners of the fourth ventricle. Step 3: a small cross (3 × 3 voxels, yellow) of approximately the width of the LC (~1–2 mm) was placed on the voxels with peak signal intensity. Step 4: a dorsal pontine tegmentum reference ROI (light blue) was defined as a 10 × 10 voxel square located 6 voxels above the more ventral (higher in the magnetic resonance axial image) of the 2 LCs and equidistantly between them. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Age and sex differences in locus coeruleus (LC) signal intensity. (A) An example of a left and right LC in the neuromelanin-sensitive T1-weighted fast-spin echo images of one younger and one older adult. For illustrative purposes only, the intensity thresholds have been adjusted to maximize the visual contrast between the LC and adjacent brainstem tissue because the mean LC signal intensities differ significantly between age groups. Because each participant's fast spin-echo image is normalized relative to the noise in his/her image, such adjustments are only meant to demonstrate that the LC is clearly delineable in both age groups. (B) Age and sex differences in LC signal intensity are displayed as bars (means) for each subgroup. Bars reflect standard errors of the means. *p < 0.05.

Fig. 3

Correlations between education, Wechsler Test of Adult Reading (WTAR) (index of verbal intelligence), and occupational attainment displayed for each age subgroup, separately. In older adults, a cognitive reserve composite score–calculated as the shared variance among the 3 reserve variables–was also correlated with locus coeruleus (LC) signal intensity. Darker bars indicate statistically significant correlation.

Fig. 4

A schematic of cognitive reserve's moderating effect on the locus coeruleus (LC)-attention association in healthy older adults. Continuous values for cognitive reserve factor scores moderated the strength of the positive relationship between LC signal intensity and attentional shifting. The negative standardized regression coefficient of the reserve × LC intensity interaction term indicated that as reserve levels linearly decreased, the association between LC signal intensity and attentional shifting strengthened significantly.