eprintid: 10064127 rev_number: 33 eprint_status: archive userid: 608 dir: disk0/10/06/41/27 datestamp: 2018-12-14 08:39:05 lastmod: 2021-09-25 22:58:30 status_changed: 2019-10-07 13:11:24 type: article metadata_visibility: show creators_name: Kim, WH creators_name: Racine, AM creators_name: Adluru, N creators_name: Hwang, SJ creators_name: Blennow, K creators_name: Zetterberg, H creators_name: Carlsson, CM creators_name: Asthana, S creators_name: Koscik, RL creators_name: Johnson, SC creators_name: Bendlin, BB creators_name: Singh, V title: Cerebrospinal fluid biomarkers of neurofibrillary tangles and synaptic dysfunction are associated with longitudinal decline in white matter connectivity: A multi-resolution graph analysis ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 keywords: DTI tractography, CSF biomarker, Longitudinal brain connectivity, Alzheimer's disease pathology, Multi-resolution analysis note: © 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/). 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. date: 2018-10-23 date_type: published official_url: https://doi.org/10.1016/j.nicl.2018.10.024 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1608813 doi: 10.1016/j.nicl.2018.10.024 pii: S2213-1582(18)30334-6 language_elements: English lyricists_name: Zetterberg, Henrik lyricists_id: HZETT94 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: NeuroImage: Clinical volume: 21 article_number: 101586 event_location: Netherlands issn: 2213-1582 citation: Kim, WH; Racine, AM; Adluru, N; Hwang, SJ; Blennow, K; Zetterberg, H; Carlsson, CM; ... Singh, V; + view all <#> Kim, WH; Racine, AM; Adluru, N; Hwang, SJ; Blennow, K; Zetterberg, H; Carlsson, CM; Asthana, S; Koscik, RL; Johnson, SC; Bendlin, BB; Singh, V; - view fewer <#> (2018) 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 , 21 , Article 101586. 10.1016/j.nicl.2018.10.024 <https://doi.org/10.1016/j.nicl.2018.10.024>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10064127/1/Zetterberg_Cerebrospinal%20fluid%20biomarkers%20of%20neurofibrillary%20tangles%20and%20synaptic%20dysfunction%20are%20associated%20with%20longitudinal%20decline%20in%20white%20matter_Proof.pdf