Patterns of anterior versus posterior white matter fractional anistotropy concordance in adult nonhuman primates: Effects of early life stress.

INTRODUCTION: Functional neuroimaging studies report global prefrontal dysconnectivity in mood disorders, supporting the notion of widespread disruptions in brain networks. Microscopic alterations in white matter (WM) tracts - which possess neuroplastic properties and play a central role in brain connectivity - are interrogated herein in the context of brain dysconnectivity. Early life stress (ELS), an antecedent to human mood disorders, induces WM alterations in volumetrics and integrity. We hypothesized that nonhuman primate infants exposed to ELS would exhibit persistent impairments in both frontal and posterior concordance of WM integrity, therefore contributing to global brain dysconnectivity. METHODS: Using a 3T MRI, diffusion tensor imaging (DTI) was performed on 21 adult male Bonnet macaques, 12 of whom had been raised under variable foraging demand (VFD) conditions and nine of whom had been raised under normative conditions (Non-VFD). As representative of anterior regions, fractional anisotropy (FA) concordance between anterior corpus callosum (ACorpusC) and anterior limb of the internal capsule (ALIC) was examined. For posterior regions, FA concordance between posterior corpus callosum (PCorpusC) and posterior limb of the internal capsule (PLICA) and between PCorpusC and occipital WM was examined. Examination of posterior FA was explored in the context of frontal markers of neuroplasticity. RESULTS: A concordant relationship for FA between left ALIC and ACorpusC was evident in Non-VFD-reared subjects, but significantly absent in VFD-reared subjects. For left posterior regions, FA concordance between PLICA and PCorpusC and occipital WM and PCorpusC was evident in VFD-reared and not Non-VFD-reared subjects. The posterior concordance in VFD was significantly distinguishable from the deficit in anterior concordance FA in VFD. CONCLUSIONS: The findings support the view that disrupted emotional integrity of the maternal-infant attachment process affects normative synchronous development of frontal white matter tracts but creates errant posterior concordance and also disrupts an inverse relationship between posterior white matter tracts and markers of neuroplasticity. We provide preliminary evidence that a concordant relationship between capsular-callosal FA may become discordant, providing a putative mechanism for prefrontal functional brain dysconnectivity.

Early life stress and macaque amygdala hypertrophy: preliminary evidence for a role for the serotonin transporter gene.

BACKGROUND: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. The primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals. METHODS: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years). RESULTS: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: "high" cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls. CONCLUSION: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.

Association between linear measurements of corpus callosum and gait in the elderly.

PURPOSE: Segmentation and diffusion-tensor-imaging of the corpus callosum (CC) have been linked to gait impairment. However, such measurements are impracticable in clinical routine. The purpose of this study was to evaluate the association between simple linear measurements of CC thickness with gait. METHODS: Two hundred and seventy-two community-dwelling subjects underwent neurological assessment and brain MRI. Mid-sagittal reformats of T1-weighted images were used to determine CC thickness. The association of measurements with clinical evaluation of gait was assessed by multivariate regression, controlling for numerous clinical and imaging confounders. Differences in CC thickness were, moreover, compared between subgroups with no, moderate or severe impairment of gait. RESULTS: In univariate analyses, thickness of the genu and body of CC but not the splenium were associated with postural stability (P < 0.01). Multivariate regression revealed thickness of CC genu as the only imaging variable independently associated with gait (P = 0.01). Genu thickness was significantly different between subjects with high and low (P = 0.0003) or high and moderate (P = 0.001) risk of fall. CONCLUSION: Atrophy of the CC genu is an imaging marker of gait impairment in the elderly suggesting higher risk of fall. Simple linear measurements of CC can help in MRI evaluation of patients with gait impairment. KEY POINTS: • Regional atrophy of the corpus callosum reflects disruption of gait regulation • Genu thickness on cranial MRI is an independent marker of gait impairment • Findings help in the MRI evaluation of patients with gait impairment.

The role of early life stress in development of the anterior limb of the internal capsule in nonhuman primates.

Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) may be effective in treating depression. Parental verbal abuse has been linked to decreased fractional anisotropy (FA) of white matter and reduced FA correlated with depression and anxiety scores. Utilizing a nonhuman primate model of mood and anxiety disorders following disrupted mother-infant attachment, we examined whether adverse rearing conditions lead to white matter impairment of the ALIC. We examined white matter integrity using Diffusion Tensor Imaging (DTI) on a 3T-MRI. Twenty-one adult male Bonnet macaques participated in this study: 12 were reared under adverse [variable foraging demand (VFD)] conditions whereas 9 were reared under normative conditions. We examined ALIC, posterior limb of the internal capsule (PLIC) and occipital white matter. VFD rearing was associated with significant reductions in FA in the ALIC with no changes evident in the PLIC or occipital cortex white matter. Adverse rearing in monkeys persistently impaired frontal white matter tract integrity, a novel substrate for understanding affective susceptibility.

A comparative analysis of structural brain MRI in the diagnosis of Alzheimer's disease.

Dementia is a debilitating and life-altering disease which leads to both memory impairment and decline of normal executive functioning. While causes of dementia are numerous and varied, the leading cause among patients 60 years and older is Alzheimer's disease. The gold standard for Alzheimer's diagnosis remains histological identification of amyloid plaques and neurofibrillary tangles within the medial temporal lobe, more specifically the entorhinal cortex and hippocampus. Although no definitive cure for Alzheimer's disease currently exists, there are treatments targeted at preserving cognition and memory while delaying continued loss of function. Alzheimer's disease exists along a spectrum of cognitive decline and is often preceded by Mild Cognitive Impairment (MCI). Patients with MCI demonstrate memory loss and cognitive impairment while still continuing normal activities of daily living, and are considered to be at increased risk for developing Alzheimer's Dementia. Identifying patients with prodromal states of Alzheimer's dementia such as MCI may allow initiation of appropriate treatment planning and delay of cognitive decline. Therefore, the need for a non-invasive early biomarker for the detection of Alzheimer's disease has never been greater. Multiple neuroimaging methods utilizing visual rating scales, volumetric measurements, and automated methods have been developed to identify, quantify, and track anatomic sequelae of Alzheimer's Disease.