Diffusion MRI tractography of the locus coeruleus-transentorhinal cortex connections using GO-ESP.

PURPOSE: The locus coeruleus (LC) is implicated as an early site of protein pathogenesis in Alzheimer's disease (AD). Tau pathology is hypothesized to propagate in a prion-like manner along the LC-transentorhinal cortex (TEC) white matter (WM) pathway, leading to atrophy of the entorhinal cortex and adjacent cortical regions in a progressive and stereotypical manner. However, WM damage along the LC-TEC pathway may be an earlier observable change that can improve detection of preclinical AD. THEORY AND METHODS: Diffusion-weighted MRI (dMRI) allows reconstruction of WM pathways in vivo, offering promising potential to examine this pathway and enhance our understanding of neural mechanisms underlying the preclinical phase of AD. However, standard dMRI analysis tools have generally been unable to reliably reconstruct this pathway. We apply a novel method, geometric-optics based entropy spectrum pathways (GO-ESP) and produce a new measure of connectivity: the equilibrium probability (EP). RESULTS: We demonstrated reliable reconstruction of LC-TEC pathways in 50 cognitively normal older adults and showed a negative association between LC-TEC EP and cerebrospinal fluid tau. Using Human Connectome Project data, we demonstrated replicability of the method across acquisition schemes and scanners. Finally, we compared our findings with the only other existing LC-TEC tractography template, and replicated their pathway as well as investigated the source of these discrepant findings. CONCLUSIONS: AD-related tau pathology may be detectable within GO-ESP-identified LC-TEC pathways. Furthermore, there may be multiple possible routes from LC to TEC, raising important questions for future research on the LC-TEC connectome and its role in AD pathogenesis.

White Matter Microstructure is Associated with Serum Clusterin and Everyday Functioning in a Sample of Nondemented Older Adults.

BACKGROUND: Although clusterin-a protein involved in lipid metabolism, amyloid beta clearance, and myelination-has been linked to gray matter atrophy within samples of older adults at risk for Alzheimer's disease, research exploring associations with white matter (WM) micro- and macro- structural markers are largely limited. OBJECTIVE: The current study explored associations between serum clusterin protein levels and WM micro- and macro- structural markers, and clarified whether variations in WM fractional anisotropy (FA) were associated with functional abilities within in a racially homogenous sample of relatively well-educated older adults free of dementia. METHODS: Participants underwent magnetic resonance imaging (MRI) brain exams and a blood draw and completed a performance-based measure of everyday functioning. Multiple linear regression adjusting for age, sex, APOE e4 positivity, and vascular risk were used to explore serum clusterin associations with WM metrics, as well clarify potential links between WM microstructure and everyday functioning. RESULTS: Higher serum clusterin was associated with lower FA in several thalamocortical (anterior and posterior internal capsule, posterior thalamic radiation; ßs = -.32 to -.37, ps = .01 to .02) and association fiber tracts (external capsule, superior longitudinal fasciculus; ßs = -.32 to -.40, ps = .02). Serum clusterin was not associated with white matter hyperintensity volume (ß = .14, p = .28), but higher FA of several WM tracts was associated with better performance on the Independent Living Scale (ßs = .37 to .53, ps = .006 to .03). CONCLUSIONS: Serum clusterin is differentially associated with WM metrics, and WM microstructure is associated with everyday functioning.

Elevated Inflammatory Markers and Arterial Stiffening Exacerbate Tau but Not Amyloid Pathology in Older Adults with Mild Cognitive Impairment.

BACKGROUND: Age-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer's disease (AD), although their interactive effects have yet to be fully examined. OBJECTIVE: The current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI). METHODS: This study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory markers were used to create an inflammation composite, and amyloid-beta 1-42 (Aß42), phosphorylated tau (p-tau), and total tau (t-tau) were quantified. RESULTS: Multiple regression analyses controlling for age, education, and APOE ɛ4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p = 0.01) and p-tau (B = 0.84, p = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aß42 (B = -1.01, p = 0.02); greater inflammation was associated with higher levels of Aß42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (p s < 0.05). CONCLUSION: PP and inflammation exert differential effects on AD CSF proteins and provide evidence that vascular risk is associated with greater AD pathology across our sample of CN and MCI older adults.

White matter compromise in autism? Differentiating motion confounds from true differences in diffusion tensor imaging.

Common findings from diffusion tensor imaging (DTI) in autism spectrum disorder (ASD) include reduced fractional anisotropy (FA), and increased mean and radial diffusivity (MD, RD) of white matter tracts. However, findings may be confounded by head motion. We examined how group-level motion matching affects DTI comparisons between ASD and typically developing (TD) groups. We included 57 ASD and 50 TD participants, comparing three subsets at increasing levels of motion-matching stringency: full sample (FS); quality-controlled (QC); and quantitatively-matched (QM). Groups were compared on diffusivity measures using Tract-Based Spatial Statistics (TBSS) and probabilistic tractography. Two methods for estimating diffusivity were compared: dti-fit and restore. TBSS: In set FS, FA was reduced in the ASD compared to the TD group throughout the right hemisphere. This effect was less extensive in set QC and absent in set QM. However, effect sizes remained stable or increased with better quality-control in some regions. Tractography: In set QM, MD was significantly higher in ASD overall and RD was higher in bilateral ILF. Effects were more robust in QM than in FS or QC sets. Effect sizes in several tracts increased with stringent quality matching. Restore improved tensor estimates, with some increases in effect sizes, but did not fully compensate for reduced quality. Findings suggest that some previously reported DTI findings for ASD may have been confounded by motion. However, effects in the tightly matched subset indicate that tract-specific anomalies probably do exist in ASD. Our results highlight the need for careful quality-control and motion-matching. Autism Res 2017, 10: 1606-1620. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.