Tau neurofibrillary tangles have a central role in the pathogenesis of Alzheimer’s Disease (AD). Mounting evidence indicates that the propagation of tau is assisted by brain connectivity with weakened white-matter integrity along the propagation pathways. Recent advances in tau positron emission tomography tracers and diffusion magnetic resonance imaging allow the visualization of tau pathology and white-matter connectivity of the brain in vivo. The current study aims to investigate how tau deposition and structural connectivity are associated with memory function in prodromal AD. In this study, tau accumulation and structural connectivity data from 83 individuals (57 cognitively normal participants and 26 participants with mild cognitive impairment) were associated with neurocognitive test scores. Statistical analyses were performed in 70 cortical/subcortical brain regions to determine: 1. the level of association between tau and network metrics extracted from structural connectivity and 2. the association patterns of brain memory function with tau accumulation and network metrics. The results showed that tau accumulation and network metrics were correlated in early tau deposition regions. Furthermore, tau accumulation was associated with worse performance in almost all neurocognitive tests performance evaluated in the study. In comparison, decreased network connectivity was associated with declines in the delayed memory recall in Craft Stories and Benson Figure Copy. Interaction analysis indicates that tau deposition and dysconnectivity have a synergistic effect on the delayed Benson Figure Recall. Overall, our findings indicate that both tau deposition and structural dysconnectivity are associated with neurocognitive dysfunction. They also suggest that tau-PET may have better sensitivity to neurocognitive performance than diffusion MRI-derived measures of white-matter connectivity.
Tau neurofibrillary tangles have a central role in the pathogenesis of Alzheimer’s Disease (AD). Mounting evidence indicates that the propagation of tau is assisted by brain connectivity with weakened white-matter integrity along the propagation pathways. Recent advances in tau positron emission tomography tracers and diffusion magnetic resonance imaging allow the visualization of tau pathology and white-matter connectivity of the brain in vivo. The current study aims to investigate how tau deposition and structural connectivity are associated with memory function in prodromal AD. In this study, tau accumulation and structural connectivity data from 83 individuals (57 cognitively normal participants and 26 participants with mild cognitive impairment) were associated with neurocognitive test scores. Statistical analyses were performed in 70 cortical/subcortical brain regions to determine: 1. the level of association between tau and network metrics extracted from structural connectivity and 2. the association patterns of brain memory function with tau accumulation and network metrics. The results showed that tau accumulation and network metrics were correlated in early tau deposition regions. Furthermore, tau accumulation was associated with worse performance in almost all neurocognitive tests performance evaluated in the study. In comparison, decreased network connectivity was associated with declines in the delayed memory recall in Craft Stories and Benson Figure Copy. Interaction analysis indicates that tau deposition and dysconnectivity have a synergistic effect on the delayed Benson Figure Recall. Overall, our findings indicate that both tau deposition and structural dysconnectivity are associated with neurocognitive dysfunction. They also suggest that tau-PET may have better sensitivity to neurocognitive performance than diffusion MRI-derived measures of white-matter connectivity
Background: Diagnosis of AD is often started via cognitive tests such as the Mini Mental Status Exam (MMSE) or Montreal Cognitive Assessment (MOCA) with the diagnosis being finalized with autopsy. Currently, positron emission tomography (PET) tracers are used to visualize tau and beta amyloid accumulation in the brain. These imaging techniques demonstrate significant correlations with cognitive decline and have been used to aid in the diagnosis of AD. Particularly, tau accumulation has been shown to progress in a distinct pattern and has been linked to white matter degeneration. We hypothesized that tau accumulation and white matter degeneration in different brain regions have unique correlation patterns with domain-specific neuropsychiatric test scores. Methods: This study included 87 older adults (57 cognitively normal subjects and 27 mild cognitive impairment) from the Indiana Alzheimer’s Disease Center. All participants underwent tau-PET ([18F] Flortaucipir PET) and diffusion MRI (dMRI) exams. Tau accumulation was quantified with tau-PET SUVR. White-matter structural connectivity (SC), which probes the integrity of white-matter connections of the brain, was quantified by metrices extracted from dMRI using network analysis. Both tau accumulation and SC measurements were quantified in 84 cortical region of interests (ROIs) and were compared to their domain specific neuropsychiatric test scores with linear regression analysis. Results: The verbal memory, visual memory, and visuospatial ability all had unique region-specific correlations with white-matter degeneration and tau accumulation. Verbal memory was solely correlated with tau accumulation. Visual memory was related to both tau accumulation and white-matter SC. Finally, visuospatial ability was only correlated with white-matter SC. Potential Impact: This data reveals that although there is a tight interplay between tau accumulation and white-matter degeneration, they affect brain functions in different ways. Specifically, grey-matter tau accumulation is associated with overall memory loss and decrease in the white-matter connectivity affects the visual-related information processing.
Background: Traditionally, the accumulation of amyloid beta peptides (Aβ) and tau proteins are considered the main pathological hallmarks of AD due to their impact on cortical microstructural organization, which leads to dendritic deficit and neuronal loss. Additionally, it is hypothesized that these pathophysiological processes may induce axonal and oligodendrocyte dysfunction exacerbating myelin impairment. The objective of this cross-sectional study is to estimate the degree of alterations in white matter (WM) microstructural organization associated with pathological proteins at the pre-clinical stage of AD. Methods: To achieve this, diffusion magnetic resonance imaging (dMRI) data and cerebrospinal fluid (CSF) samples were obtained from 84 patients determined to be cognitively normal using neurophysiological tests. CSF samples were analyzed for levels of CSF total tau (T-tau), phosphorylated tau (p-tau181), and Aβ42. The participants were then divided into two groups based on their biomarker (BM) levels (BM+: T-tau/Aβ42 ³ 0.18, and BM-: T-tau/Aβ42 < 0.18). The level of WM integrity was determined through Free Water Eliminating Diffusion Tensor Imaging (FWEDTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) analysis of the dMRI data. Results: Comparisons of WM integrity between the two groups showed a significant reduction in diffusivity in BM+ participants, relative to the BM- group. Additionally, region of interest (ROI)/cluster-based analysis displayed significant associations between levels of CSF biomarkers (T-tau, T-tau/Aβ42, and p-tau/Aβ42) with sophisticated diffusion metrices in multiple regions. CSF Aβ42 alone lacked significant association with white matter alterations. Conclusion: These results suggest that the processes behind pathological protein accumulation influence WM integrity in pre-symptomatic AD, and are primarily driven by tau proteins. Therefore, CSF models which include both measures of tau and Aβ42 are better indicators of AD in its non-dormant stages.
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