Neural reserve, neuronal density in the locus ceruleus, and cognitive decline

Abstract

Objective: To test the hypothesis that higher neuronal density in brainstem aminergic nuclei contributes to neural reserve.

Methods: Participants are 165 individuals from the Rush Memory and Aging Project, a longitudinal clinical-pathologic cohort study. They completed a mean of 5.8 years of annual evaluations that included a battery of 19 cognitive tests from which a previously established composite measure of global cognition was derived. Upon death, they had a brain autopsy and uniform neuropathologic examination that provided estimates of the density of aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area plus summary measures of neuronal neurofibrillary tangles and Lewy bodies from these nuclei and medial temporal lobe and neocortex.

Results: Neuronal densities in each nucleus were approximately normally distributed. In separate analyses, higher neuronal density in each nucleus except the ventral tegmental area was associated with slower rate of cognitive decline, but when modeled together only locus ceruleus neuronal density was related to cognitive decline (estimate = 0.003, SE = 0.001, p < 0.001). Higher densities of tangles and Lewy bodies in these brainstem nuclei were associated with faster cognitive decline even after controlling for pathologic burden elsewhere in the brain. Locus ceruleus neuronal density, brainstem tangles, and brainstem Lewy bodies had independent associations with rate of cognitive decline. In addition, at higher levels of locus ceruleus neuronal density, the association of Lewy bodies with cognitive decline was diminished.

Conclusion: Density of noradrenergic neurons in the locus ceruleus may be a structural component of neural reserve.

Figure 1. Diagram of the posterior aspect of the brainstem extending rostrally from the level of the superior colliculus to the caudal end of the fourth ventricle

The green lines indicate the limits of the 4 consecutive blocks taken of the brainstem. The location of the dorsal raphe nucleus (DRN) and the right locus ceruleus (LC) are shown.

Figure 2. Cognitive decline

(A) Predicted 6-year paths of cognitive decline with low (10th percentile, red line), medium (50th percentile, black line), or high (90th percentile, green line) levels of locus ceruleus neuronal density adjusted for age at death, sex, and education. (B) Distribution of annual rate of cognitive decline at lower (below median) or higher (above median) levels of locus ceruleus neuronal density in those with (pink) or without (green) brainstem Lewy bodies adjusted for age at death, sex, and education.