Association of Retinal and Macular Damage with Brain Atrophy in Multiple Sclerosis

et al. (2011) Association of Retinal and Macular Damage with Brain Atrophy in Multiple Sclerosis. PLoS ONE 6(4): e18132. doi:10.1371/journal.pone.0018132 Association of Retinal and Macular Damage with Brain Atrophy in Multiple Sclerosis Jan Do rr 0 Klaus D. Wernecke 0 Markus Bock 0 Gunnar Gaede 0 Jens T. Wuerfel 0 Caspar F. Pfueller 0 Judith Bellmann-Strobl 0 Alina Freing 0 Alexander U. Brandt 0 Paul Friedemann 0 Rafael Linden, Universidade Federal do Rio de Janeiro, Brazil 0 1 NeuroCure Clinical Research Center, Charite - Universitaetsmedizin Berlin , Berlin, Germany , 2 Sophisticated Statistical Analysis GmbH and Charite - Universitaetsmedizin Berlin , Berlin, Germany , 3 Institute of Neuroradiology, University Luebeck, Luebeck, Germany, 4 Experimental and Clinical Research Center, Charite - Universitaetsmedizin Berlin and Max-Delbru ck Center for Molecular Medicine Berlin , Berlin, Germany, 5 gfnmediber GmbH, Berlin , Germany Neuroaxonal degeneration in the central nervous system contributes substantially to the long term disability in multiple sclerosis (MS) patients. However, in vivo determination and monitoring of neurodegeneration remain difficult. As the widely used MRI-based approaches, including the brain parenchymal fraction (BPF) have some limitations, complementary in vivo measures for neurodegeneration are necessary. Optical coherence tomography (OCT) is a potent tool for the detection of MS-related retinal neurodegeneration. However, crucial aspects including the association between OCT- and MRI-based atrophy measures or the impact of MS-related parameters on OCT parameters are still unclear. In this large prospective cross-sectional study on 104 relapsing remitting multiple sclerosis (RRMS) patients we evaluated the associations of retinal nerve fiber layer thickness (RNFLT) and total macular volume (TMV) with BPF and addressed the impact of diseasedetermining parameters on RNFLT, TMV or BPF. BPF, normalized for subject head size, was estimated with SIENAX. Relations were analyzed primarily by Generalized Estimating Equation (GEE) models considering within-patient inter-eye relations. We found that both RNFLT (p = 0.019, GEE) and TMV (p = 0.004, GEE) associate with BPF. RNFLT was furthermore linked to the disease duration (p,0.001, GEE) but neither to disease severity nor patients' age. Contrarily, BPF was rather associated with severity (p,0.001, GEE) than disease duration and was confounded by age (p,0.001, GEE). TMV was not associated with any of these parameters. Thus, we conclude that in RRMS patients with relatively short disease duration and rather mild disability RNFLT and TMV reflect brain atrophy and are thus promising parameters to evaluate neurodegeneration in MS. Furthermore, our data suggest that RNFLT and BPF reflect different aspects of MS. Whereas BPF best reflects disease severity, RNFLT might be the better parameter for monitoring axonal damage longitudinally. Longitudinal studies are necessary for validation of data and to further clarify the relevance of TMV. - Funding: This work was supported by grants from the Excellence Cluster 257 of the German Research Foundation to NeuroCure Clinical Research Center, grant KF2286101FO9 from the German Ministry of Economics to NeuroCure Clinical Research Center and gfnmediber GmbH (www.gfnmediber.de) and a limited research grant by TEVA Pharma GmbH, Germany (www.teva-deutschland.de). These funders played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Besides their scientific affiliation at the Charite, Alexander U. Brandt and Klaus-Dieter Wernecke are employed by gfnmediber (AU Brandt) and SoStAna (KD Wernecke, www.sostana.com). Alexander U. Brandt contributed to this project (study design, statistical analysis and preparation of the manuscript) in his role as scientist and not as employee of gfnmediber GmbH. Apart from partial funding (grant KF2286101FO9 from the German Ministry of Economics) the company gfnmediber GmbH had no further role in this project. Klaus-Dieter Wernecke contributed to this project (study design, statistical analysis) in his role as scientist at the Charite and not as CEO of SoStAna. The company SoStAna itself had no role in this project. Competing Interests: Alexander U. Brandt is deputy CEO of gfnmediber GmbH and guest scientist at the NeuroCure Clinical Research Center (NCRC). Alexander U Brandt contributed to the study merely in his role of a guest scientist at the NCRC. Klaus-Dieter Wernecke is CEO of Sophisticated Statistical Analysis (SoStAna) and scientist at the Charite, Berlin. Klaus-Dieter Wernecke contributed to the study merely in his role as a scientist at the Charite. There are no patents, products in development or marketed products to declare with the current study and these affiliations did not alter the authors adherence to all the PLoS ONE policies on sharing data and materials. All other authors have declared that no competing interests exist. . These authors contributed equally to this work. Increasing evidence documents that neuronal and axonal damage within the central nervous system (CNS) contributes substantially to the development of permanent disability in multiple sclerosis (MS) [1,2,3]. However, in vivo quantification and longitudinal monitoring of neurodegenerative processes remain a challenging task. Whole brain atrophy expressed by brain parenchymal fraction (BPF) is a frequently used MRI-based surrogate parameter for neurodegeneration within the CNS [4,5,6] and an inverse relation of BPF and disability progression has been consistently demonstrated [7,8]. However, all MRIbased measures of brain atrophy have some important disadvantages. Besides limited availability, time consumption and costs, crucial confounders such as hydration status, inflammation, demyelination and age have to be accounted for [5]. Thus, a need for reliable, inexpensive and easily assessable complementary surrogate markers for neuroaxonal degeneration still remains. During the past two decades, optical coherence tomography (OCT) has emerged into a fascinating tool for the non invasive and reproducible in vivo studying of retinal neuroaxonal damage [9]. In MS patients, OCT has been consistently shown to detect thinning of the peripapillary retinal nerve fiber layer (RNFL) which is most probably due to a diffuse damage of retinal axons and at least in part independent of a previous optic neuritis (ON) [10,11,12]. Moreover, the determination of total macular volume (TMV) has been suggested as a marker for neuronal loss in MS patients [13]. Therefore, OCT might be a valuable tool for quantification and monitoring of both axonal and neuronal damage in MS [14,15]. However, data on association between retinal nerve fiber layer thickness (RNFLT) and MS-determining parameters such as disease severity and disease duration are still inconsistent [15]. Whereas some studies found an association between R (...truncated)