White Matter Fractional Anisotropy in a Nonhuman Primate Model of Early Alzheimer’s Disease‐like Neuropathology: Relationships with Social Status and Physiologic Measures of Stress Responses

Abstract

AbstractBackgroundPsychosocial stress is associated with micro‐ and macrostructural brain changes that may increase risk of Alzheimer’s disease (AD). White matter (WM) appears particularly vulnerable, and changes in white matter integrity are an early sign of AD pathogenesis. Cynomolgus macaques (Macaca fascicularis) have complex central nervous systems and naturally develop early AD‐like neuropathology with age. Female macaques form social status hierarchies in which subordinates exhibit behavioral and physiological signs of stress, and increased stress‐related pathologies similar to humans. Nonhuman primate studies provide a useful platform in which to assess relationships between stress and brain health is a well‐controlled environment with limited outside influences. Thus, these nonhuman primates are useful translational models for studying relationships of psychosocial stress with early AD‐like neuropathology.MethodUsing diffusion tensor imaging, we examined the relationship between psychosocial stress and fractional anisotropy (index of WM microstructural integrity (FA)) in 38 middle‐aged female cynomolgus macaques living in small social groups. Subjects were classified as either dominant or subordinate based upon the outcomes of agonistic interactions. FA in several regions of interest (ROIs): splenium, body, and genu of the corpus callosum (CC), frontal, temporal, occipital, and total cerebral and cerebellar white matter was assessed in relation to social status and several contemporaneous measures of stress physiology (blood pressure, resting cortisol, and heart rate variability (HRV)).ResultRepeated measures ANOVA using left and right ROIs as a repeated measure showed that dominants had significantly higher FA than subordinates in the genu and splenium of the CC, and the occipital and frontal cortices (all p<0.05). Dominants also had higher FA, on average, in the body of CC (p=0.07) and cerebrum (p=0.10), although these differences were not significant. Dominants and subordinates did not differ in temporal or cerebellar FA (both p>0.7). FA was inversely correlated with blood pressure, directly correlated with HRV (p’s<0.05), but not correlated with serum cortisol.ConclusionPsychosocial stress of subordination, as well as physiologic indices of stress responses, was associated with diminished WM integrity in several brain regions. These studies lay the groundwork for investigations of interventions on psychosocial stress to reduce AD risk later in life.