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

Won Hwa Kim, Annie M. Racine, Nagesh Adluru, Seong Jae Hwang, Kaj Blennow, Henrik Zetterberg, Cynthia M. Carlsson, Sanjay Asthana, Rebecca L. Koscik, Sterling C. Johnson, Barbara B. Bendlin, Vikas Singh

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

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 (Aβ42 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.

Original languageEnglish
Article number101586
JournalNeuroImage: Clinical
Volume21
DOIs
Publication statusPublished - 2019

Bibliographical note

Funding Information:
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.

Funding Information:
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 S?derberg'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.

Funding Information:
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.

Publisher Copyright:
© 2018 The Authors

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging
  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience

Fingerprint

Dive into the research topics of 'Cerebrospinal fluid biomarkers of neurofibrillary tangles and synaptic dysfunction are associated with longitudinal decline in white matter connectivity: A multi-resolution graph analysis'. Together they form a unique fingerprint.

Cite this