Amyloid burden accelerates white matter degradation in cognitively normal elderly individuals

Abstract

Alterations in parietal and temporal white matter microstructure derived from diffusion tensor imaging occur in preclinical and clinical Alzheimer's disease. Amyloid beta (Aβ) deposition and such white matter alterations are two pathological hallmarks of Alzheimer's disease. However, the relationship between these pathologies is not yet understood, partly since conventional diffusion MRI methods cannot distinguish between cellular and extracellular processes. Thus, we studied Aβ‐associated longitudinal diffusion MRI changes in Aβ‐positive (N = 21) and Aβ‐negative (N = 51) cognitively normal elderly obtained from the Alzheimer's Disease Neuroimaging Initiative dataset using linear mixed models. Aβ‐positivity was based on Alzheimer's Disease Neuroimaging Initiative amyloid‐PET recommendations using a standardized uptake value ratio cut‐off of 1.11. We used free‐water imaging to distinguish cellular and extracellular changes. We found that Aβ‐positive subjects had increased baseline right uncinate fasciculus free‐water fraction (FW), associated with worse baseline Alzheimer's disease assessment scale scores. Furthermore, Aβ‐positive subjects showed faster decrease in fractional anisotropy (FW‐corrected) in the right uncinate fasciculus and faster age‐dependent right inferior longitudinal fasciculus FW increases over time. Right inferior longitudinal fasciculus FW increases were associated with greater memory decline. Importantly, these results remained significant after controlling for gray and white matter volume and hippocampal volume. This is the first study to illustrate the influence of Aβ burden on early longitudinal (in addition to baseline) white matter changes in cognitively normal elderly individuals at‐risk of Alzheimer's disease, thus underscoring the importance of longitudinal studies in assessing microstructural alterations in individuals at risk of Alzheimer's disease prior to symptoms onset.

Longitudinal trajectory of Amyloid‐related hippocampal subfield atrophy in nondemented elderly

“…Several possibilities may be proposed. Specifically, key cortical regions for earliest Aβ deposition (e.g., PCC/precuneus, orbital frontal; Palmqvist et al, ) could connect to hippocampus via white matter tracts (e.g., from the orbital frontal via uncinate fasciculus, and from the PCC/retrosplenial via cingulum; Greicius, Supekar, Menon, & Dougherty, ; Vipin et al, ). This implies a structural pathway where abnormal Aβ may modulate.…”

“…This implies a structural pathway where abnormal Aβ may modulate. Indeed, Aβ has been associated with longitudinal impairment of white matter integrity before dementia (Vipin et al, ). Also, reduced precuneus–hippocampus functional connectivity has been found in nondemented participants with positive Aβ compared with those with negative Aβ (Sheline et al, ), providing a potential functional pathway.…”

Bundle-specific associations between white matter microstructure and Aβ and tau pathology at their connecting cortical endpoints in older adults at risk of Alzheimer’s disease

“…The classical degeneration pattern accompanying disease progression is characterized by lower anisotropy and higher diffusivity, representing loss of coherence in the white matter microstructure with AD progression (Caso et al, 2016;Sexton et al, 2011). This pattern of white matter degeneration develops invariably along the AD spectrum (Amlien and Fjell, 2014;Pereira et al, 2019), with associations often becoming detectable only in the mild cognitive impairment and dementia stages (Mito et al, 2018;Song et al, 2018;Wang et al, 2019;Wen et al, 2019), and very few in Aβ-positive cognitively normal participants (Rieckmann et al, 2016;Vipin et al, 2019). However, our consistent pattern of more restricted diffusion (higher FA and lower MD) being associated with more pathology in three bundles suggests that microstructural alterations captured with diffusion MRI might differ in the preclinical vs. the symptomatic phase of AD, during which severe and irreversible atrophy has occurred.…”

Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients

“…10 As such, free water imaging might be able to disentangle the effects of AD and SVD. [11][12][13][14] Previous studies using DTI or free water imaging were limited by the lack of biomarker evidence of AD pathology or insufficient consideration of mixed pathology. Assessing the individual contributions of AD and SVD toward diffusion MRI alterations requires a systematic study covering the entire spectrum of "pure AD," mixed disease, and "pure SVD.…”