Using Diffusion Tensor Imaging and Mixed-Effects Models to Investigate Primary and Secondary White Matter Degeneration in Alzheimer's Disease and Mild Cognitive Impairment

Article type: Research Article

Authors: O'Dwyer, Laurence^{a; *} | Lamberton, Franck^b | Bokde, Arun L.W.^c | Ewers, Michael^d | Faluyi, Yetunde O.^{e; f} | Tanner, Colby^g | Mazoyer, Bernard^{b; h; i} | O'Neill, Des^j | Bartley, Máiréad^j | Collins, D. Rónán^j | Coughlan, Tara^j | Prvulovic, David^a | Hampel, Harald^a

Affiliations: [a] Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Frankfurt, Germany | [b] Centre for Imaging-Neurosciences and Applications to Pathologies, CNRS, CEA, University of Caen and Paris Descartes, France | [c] Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Lloyd Building, Trinity College Dublin, Dublin, Ireland | [d] Department of Radiology, VA Medical Center, University of California-San Francisco, San Francisco, CL, USA | [e] Liaison Psychiatry Service, Addenbrooke's Hospital, Cambridge, UK | [f] Cambridgeshire and Peterborough NHS Foundation Trust, UK | [g] Department of Zoology, Trinity College Dublin, Dublin, Ireland | [h] Centre Hospitalier Universitaire, Caen, France | [i] Institut Universitaire de France, Paris, France | [j] Department of Medical Gerontology, Trinity College Dublin, Dublin, Ireland

Correspondence: [*] Correspondence to: Laurence O'Dwyer, Laboratory of Neuroscience (Neuroimaging and Neurophysiology Section), Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt, Germany. Tel.: +44 (0) 69 6301 4864; Fax: +44 (0) 69 6301 3833; E-mail: larodwyer@gmail.com.

Abstract: White matter (WM) degeneration in Alzheimer's disease (AD) and mild cognitive impairment (MCI) may be a key indicator of early damage in AD. Here, we analyzed WM diffusion tensor data using Tract-Based Spatial Statistics in conjunction with mixed-effects models. Four indices of diffusion were assessed in 61 healthy control, 19 non-amnestic MCIs, 14 amnestic MCIs, and 9 AD patients. The aim of the study was to use advanced mixed-effects models to investigate the retrogenesis hypothesis of AD, which suggests that tracts that are late to myelinate in ontogenetic development are the earliest to be affected in AD. Our results show that a number of late-myelinating pathways, including the parahippocampal region and the inferior longitudinal fasciculus, were predominantly affected by changes in WM volume. Conversely, early-myelinating pathways were found to be affected by a combination of both WM and gray matter (GM) atrophy. A model of the entire WM structure of the brain returned GM models for two indices of diffusion, suggesting that more complex regional landscapes of diffusion lie hidden beneath a global analysis of the entire brain. Our results warn against an explanation of white matter damage that points simply to one of two mechanisms: secondary degeneration or direct damage of myelin. We suggest that tracts may be affected by both mechanisms, with the balance depending on whether tracts are early or late-myelinating. A greater understanding of the pattern of WM changes in AD may prove useful for the early detection of AD.

Keywords: Alzheimer's disease, diffusion tensor imaging, mild cognitive impairment, mixed models, statistical models, tract based spatial statistics

DOI: 10.3233/JAD-2011-110137

Journal: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 667-682, 2011