Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: A multimodal imaging investigation

Abstract

Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (Aβ+), amyloid indeterminate (Aβi), or amyloid negative (Aβ−) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ− in all three ROIs and in Aβi compared to Aβ− in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses showing that cognitive function in these participants is not associated with any of the four DTI metrics, the present results suggest an early relationship between PiB and DTI, which may be a meaningful indicator of the initiating or compensatory mechanisms of AD prior to cognitive decline.

Measuring Cortical Connectivity in Alzheimer’s Disease as a Brain Neural Network Pathology: Toward Clinical Applications

“…Amyloid biomarker positivity with absence of gray matter neurodegeneration or cognitive impairment showed no effect on whole brain FA. (Racine et al, 2014) DTI, Amyloid-PET FA was associated with whole brain amyloid load in long association fibers and intracortical projecting fibers in 139 cognitively healthy subjects.…”

“…Other recent studies examined white matter changes in asymptomatic individuals showing biomarker evidence of amyloid or tau pathology (Bendlin et al, 2012;Chao et al, 2013;Gold et al, 2014;Kantarci et al, 2014;Molinuevo et al, 2014;Racine et al, 2014;Stenset et al, 2011). These cross-sectional studies of at-risk populations are now increasingly being complemented by longitudinal follow-up studies that allow relating the detected imaging abnormalities to future clinical outcomes Fletcher et al, 2013;Mielke et al, 2012;Zhuang et al, 2012).…”

High‐angular resolution diffusion imaging tractography of cerebellar pathways from newborns to young adults

“…Although several techniques to assess white matter development have been developed in addition to diffusion MR tractography (Ball et al., 2013; O'Muircheartaigh et al., 2014), advantages of diffusion tractography include the detection of three‐dimensional fiber bundle pathways. Many research studies have investigated white matter pathways in adults using diffusion tractography (Cercignani, Embleton, Parker, & Bozzali, 2012; Chao et al., 2009; Jin et al., 2011; Racine et al., 2014; Thong et al., 2014; Trojsi et al., 2013; Varentsova, Zhang, & Arfanakis, 2014). However, there have been far fewer studies on the development of pathways from birth to adult ages.…”

Simultaneous changes in gray matter volume and white matter fractional anisotropy in Alzheimer’s disease revealed by multimodal CCA and joint ICA

“…Most of the previously published studies only utilized one imaging modality and used univariate approaches such as region of interest, voxel-based morphometry (VBM) or tract-based spatial statistics (TBSS) to analyze structural MRI or DTI data. More recently, a number of studies employed different imaging modalities but analyzed each imaging dataset separately to investigate the fundamental pathology of AD (Wang et al, 2013, Balachandar et al, 2014, Racine et al, 2014). In contrast, multimodal fusion methods can extract simultaneous information by combining multiple neuroimaging datasets into one joint analysis to better identify the hidden covariant relationships among multiple morphological measurements in AD.…”