Cerebrospinal fluid biomarkers of neurofibrillary tangles and synaptic dysfunction are associated with longitudinal decline in white matter connectivity: A multi-resolution graph analysis [NeuroImage: Clinical]


Abstract. In addition to the development of beta amyloid plaques and neurofibrillary tangles, Alzheimer's disease (AD) involves the loss of connecting structures including degeneration of myelinated axons and synaptic connections. However, the extent to which white matter tracts change longitudinally, particularly in the asymptomatic, preclinical stage of AD, remains poorly characterized. In this study we used a novel graph wavelet algorithm to determine the extent to which microstructural brain changes evolve in concert with the development of AD neuropathology as observed using CSF biomarkers. A total of 118 participants with at least two diffusion tensor imaging (DTI) scans and one lumbar puncture for CSF were selected from two observational and longitudinally followed cohorts. CSF was assayed for pathology specific to AD (AB42 and phosphorylated-tau), neurodegeneration (total-tau), axonal degeneration (neurofilament light chain protein; NFL), and synaptic degeneration (neurogranin). Tractography was performed on DTI scans to obtain structural connectivity networks with 160 nodes where the nodes correspond to specific brain regions of interest (ROIs) and their connections were defined by DTI metrics (i.e., fractional anisotropy (FA) and mean diffusivity (MD)). For the analysis, we adopted a multi-resolution graph wavelet technique called Wavelet Connectivity Signature (WaCS) which derives higher order representations from DTI metrics at each brain connection. Our statistical analysis showed interactions between the CSF measures and the MRI time interval, such that elevated CSF biomarkers and longer time were associated with greater longitudinal changes in white matter microstructure (decreasing FA and increasing MD). Specifically, we detected a total of 17 fiber tracts whose WaCS representations showed an association between longitudinal decline in white matter microstructure and both CSF p-tau and neurogranin. While development of neurofibrillary tangles and synaptic degeneration are cortical phenomena, the results show that they are also associated with degeneration of underlying white matter tracts, a process which may eventually play a role in the development of cognitive decline and dementia.



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Figure 1: Visualization of identified brain connections whose longitudinal MD changes are dependent on p-tau (i.e. ptau x change in Time). Top: visualization of tractography generated tracts from the identified connectivity where the tracts in the same color belong to the same connectivity, Bottom: lines representing the identified connections with thickness corresponding to the p-values, where thicker line corresponds to lower p-value and ROI indices. Left: top view, Middle: left view, Right: right view.


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Figure 2: Visualization of identified brain connections whose longitudinal MD changes are dependent on neurogranin (i.e., neurogranin x change in Time). Top: visualization of tractography generated tracts from the identified connectivity where the tracts in the same color belong to the same connectivity, Bottom: lines representing the identified connections with thickness corresponding to the p-values. Thicker line corresponds to lower p-value. Left: top view, Middle: left view, Right: right view.


gloom
Figure 3: Visualization of the identified brain connections whose longitudinal FA changes are dependent on neurogranin (i.e., neurogranin x change in Time). Top: visualization of tractography generated tracts from the identified connectivity where the tracts in the same color belong to the same connectivity, Bottom: lines representing the identified connections with thickness corresponding to the p-values. Thicker line corresponds to lower p-value. Left: top view, Middle: left view, Right: right view.


References:
[1] Won Hwa Kim, Annie M. Racine, Nagesh Adluru, Seong Jae Hwang, Kaj Blennow, Henrik Zetterberg, Cyhthia M. Carlsson, Sanjay Asthana, Rebecca L. Koscik, Sterling C. Johnson, Barbara B. Bendlin, Vikas Singh, "Cerebrospinal fluid biomarkers of neurofibrillary tangles and synaptic dysfunction are associated with longitudinal decline in white matter connectivity: A multi-resolution graph analysis", NeuroImage: Clinical, 2018. [NeuroImage: Clinical]



Acknowledgment:
This research was supported by the National Institutes of Health (R01AG040396, R01AG037639, R01AG021155, R01AG027161, P50AG033514), by a Clinical and Translational Science Award (UL1RR025011) to the University of Wisconsin, Madison, the Center for Predictive Computational Phenotyping; and by the Swedish Research Council, the Swedish Brain Foundation, the Knut and Alice Wallenberg Foundation, and Torsten Söderberg's Foundation to the University of Gothenburg. Portions of this research were supported by a NSF CAREER Award to Singh and the Veterans Administration including facilities and resources at the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital, Madison, WI.