Locus coeruleus hypopigmentation is associated with an increased risk of cerebral microangiopathy in autopsy cases with cognitive impairment.

Abstract

The locus coeruleus (LC) is the main source of noradrenaline (NA) production in the brain, and one of the earliest sites of hyperphosphorylated tau in Alzheimer's disease (AD). LC degeneration is a common feature of AD. The NA LC neurons innervate the cerebrovasculature and play an important role in neurovascular coupling. Therefore, LC degeneration has been posited to contribute to vascular dysfunction and remodeling. However, this hypothesis has been rarely studied. Therefore, we explored associations between LC degeneration and microangiopathy in cases with cognitive impairment from a large human neuropathology dataset. We included data from participants with significant cognitive and/or behavioral impairment (determined by clinician(s) during visit closest to autopsy) from the National Alzheimer's Coordinating Center database (Uniform Data Set 2005 through February 2020). Participants with non-AD tauopathies or other pathologic diagnoses were excluded. Generalized estimating equations for logistic regression were used to examine associations between LC degeneration (dichotomized as moderate or severe vs none to mild LC hypopigmentation) as independent variable, and cerebral amyloid angiopathy (CAA) or arteriolosclerosis (dichotomized as moderate or severe vs none or mild) as dependent variable. Analyses were corrected for age at death, sex, AD neuropathologic change (ADNC) (dichotomized as intermediate or high vs not or low), Lewy body pathology (present vs absent), and presence of vascular (hypertension, hypercholesterolemia, angina pectoris) or genetic (ApoE4 genotype) risk factors. Cases with missing data on any of the variables of interest or covariates were excluded. We assumed a logit link function for binary outcome with an exchangeable correlation structure to account for within-center correlation, using package "gee" for R statistical software. The analyses included n=617 individuals (see table 1 for case characteristics). LC degeneration predicted an increased risk of both CAA (B (SE) = 0.47(0.19), p<0.05; OR [95% CI] = 1.61 [1.10; 2.35]), and arteriolosclerosis (B (SE) = 0.42 (0.20), p<0.05; OR [95% CI] = 1.52 [1.03; 2.24]) (table 2). LC degeneration may be associated with an increased risk for developing microvascular pathology, independent of other common pathologies. Degeneration of the LC-NA system may form an important missing link between vascular and amyloid pathology.