Multisite longitudinal reliability of tract-based spatial statistics in diffusion tensor imaging of healthy elderly subjects
Introduction
Diffusion tensor imaging (DTI) is a quantitative MRI technique widely used for the in vivo characterization of white matter microstructural organization (Ciccarelli et al., 2008, Mori and Zhang, 2006). DTI can be applied to investigate both normal and pathological conditions, and in longitudinal studies it can measure changes of white matter tissue properties in normal aging (Lebel and Beaulieu, 2011, Sullivan and Pfefferbaum, 2007, Sullivan et al., 2010, Westlye et al., 2010) as well as in brain diseases like for example Alzheimer's Disease (Kantarci et al., 2010, Mielke et al., 2009, Scola et al., 2010, Teipel et al., 2010), Huntington's Disease (Magnotta et al., 2009, Sritharan et al., 2010, Weaver et al., 2009), multiple sclerosis (Calabrese et al., 2011, Harrison et al., 2011, Rashid et al., 2008, Sage et al., 2009), stroke recovery (Wang et al., 2006) and traumatic brain injury (Sidaros et al., 2008). Such longitudinal DTI studies can be used to test and develop DTI-based biomarker models of disease progression/recovery, which may be of great utility in better understanding physiopathology as well as for evaluating therapeutic effects.
DTI allows the description of tissue microstructures modeling the Gaussian diffusion properties of water and the detection of white matter lesions (Basser and Pierpaoli, 1996). The most commonly used DTI metrics in clinical studies are fractional anisotropy (FA) and mean diffusivity (MD). Complementary information about white matter structure can be obtained from axial (AD) and radial (RD) diffusivity which, with some limitations, are considered indices of axonal injury and demyelination, respectively (Song et al., 2005, Wheeler-Kingshott and Cercignani, 2009). In addition to these diffusion metrics, orientation information in white matter tracts can be obtained using more advanced DTI acquisition and analysis methods, for example with probabilistic tractography (Behrens et al., 2003, Parker et al., 2003), diffusion spectrum imaging (Wedeen et al., 2005) and high angular resolution methods (Wedeen et al., 2008). These methods, however, typically require longer acquisition times and/or specialized MRI sequences not always available on clinical scanners, and their implementations can therefore be challenging in large multi-centric longitudinal studies, particularly when involving elderly subjects. For these reasons this study focuses on standard DTI acquisitions and their scalar derived metrics (FA, MD, AD, RD).
Longitudinal multi-center MRI studies are becoming an increasingly common strategy to collect large datasets distributing the data acquisition load across multiple partners (Van Horn and Toga, 2009). Moreover, longitudinal studies reduce the between subject variability because each subject is his/her own control. One critical factor that limits the sensitivity to detect changes in any longitudinal study is the reproducibility of repeated measures. Obtaining reproducible quantitative results from DTI data is not trivial given that the final results are sensitive to a large number of acquisition and analysis factors (Jones and Cercignani, 2010). Various aspects of DTI reproducibility have been investigated, including basic reproducibility measures of different populations (Bonekamp et al., 2007, Ciccarelli et al., 2003, Heiervang et al., 2006, Marenco et al., 2006), evaluation of the effects of region of interest (ROI) drawing protocols (Wakana et al., 2007), effects of signal averaging (Farrell et al., 2007), head motion effects (Yendiki et al., 2013), as well as the effects of various acquisition parameters like for example b-value (Bisdas et al., 2008), diffusion weighting scheme (Landman et al., 2007, Vaessen et al., 2010), voxel size (Papinutto et al., 2013), and MRI scanner effects (Brander et al., 2010, Pagani et al., 2010, Pfefferbaum et al., 2003, Vollmar et al., 2010, White et al., 2011, Zhu et al., 2011).
However, despite the wide use of DTI as a tool to assess white matter integrity in 3 T MRI studies, across-session test–retest reliability of diffusion measures on subjects in stable conditions has not been thoroughly investigated using multiple MRI systems. Across-session reproducibility is useful to estimate the effective reproducibility errors that are part of a longitudinal study, since across-session acquisitions include additional sources of variance like MRI system instabilities, differences in head positioning and re-positioning within the RF coil, differences in automated acquisition procedures like auto shimming, as well as potential effects from how different operators follow instructions to execute the same acquisition protocol. These variability sources are negligible in within-session reproducibility studies. Table 1 outlines studies that, to the best of our knowledge, have reported across-session test–retest reproducibility measures of diffusion data derived from adult healthy volunteers using 3 T systems. These studies are limited to few sites with identical 3 T scanners (Huang et al., 2012, Takao et al., 2012, Vollmar et al., 2010), focused mainly on young subjects (< 40 years, except Takao et al., 2012), using DTI analysis mostly based on manual ROIs (Bisdas et al., 2008, Jansen et al., 2007) or aimed at evaluating MRI software upgrade effects (Fox et al., 2012). In other words, the impact of across-session reproducibility errors of DTI metrics derived from multi-site longitudinal 3 T studies is not clearly defined, in particular with the commonly used tract-based spatial statistics (TBSS) analysis (Smith et al., 2006). TBSS is particularly attractive for longitudinal voxel-wise analysis of DTI data given that individual diffusion parameter maps are projected onto a group-wise skeleton constructed from FA data to account for residual misalignments among individual white matter tracts in multiple measures and multiple subjects. These issues are relevant to the PharmaCog project, a new industry-academic European project aimed at identifying biomarkers sensitive to symptomatic and disease modifying effects of drugs for Alzheimer's disease (http://www.alzheimer-europe.org/FR/Research/PharmaCog).
The aims of the present study were the following: i) to implement a multi-site 3 T MRI data acquisition protocol for diffusion analysis (10 different MRI sites covering three common clinical MRI vendors in Europe), ii) to acquire across-session test–retest data (2 acquisitions at least one week apart) from a population of healthy stable elderly subjects (5 subjects per MRI site), and iii) to evaluate and compare the across-session reproducibility of FA, MD, AD and RD diffusivities within and across MRI sites using both voxel-based TBSS and an atlas-based ROI analyses. This multi-site DTI study is unique in that it characterizes brain diffusion reproducibility metrics particularly relevant to multi-center longitudinal studies of brain disease (within-site across-session reproducibility in healthy elderly subject) derived from both full brain voxel-based TBSS and atlas-based ROIs using a wide range of clinical 3 T scanners (Table 2). The test–retest raw DTI data from the 10 MRI sites is made publicly available (100 brain volumes).
Section snippets
Materials and methods
Several aspects of the subjects, study design and data preparation steps used in this diffusion study were already described in a recent morphometry study (Jovicich et al., 2013) but are here repeated for completeness and with the appropriate modifications.
Results
In this multi-site 3 T study (10 clinical scanners from different vendors) we estimated the test–retest reliability (within-site, across two separate sessions at least a week apart) of diffusion measures derived from healthy elderly DTI data (FA, MD, radial and axial diffusivities). Both full brain (TBSS) and ROI (atlas-based) approaches were used.
The 50 subjects enrolled (Table 2) resulted to be all Caucasian with similar age distributions except for site 6 (younger group, mean age 52.4 ± 1.5
Discussion
In this Pharmacog Consortium study, we found that the test–retest reliability/variability of DTI metrics estimated with TBSS in a 3 T consortium using vendor provided sequences is consistent across sites despite the heterogeneity of MRI scanner configurations. This suggests that pooling DTI data from longitudinal multi-site studies has a potential for accelerating the evaluation of biomarkers related to water diffusion changes. We had three main findings: (1) in a group of healthy stable elderly
Conclusions
Longitudinal multisite neuroimaging designs are typically used to identify differential tissue property changes associated with normal development, plasticity or disease progression/regression. The reliability of neuroanatomical measurements over time and across MRI sites is crucial for the statistical power of longitudinal studies. The main result of this multi-site study with ten 3 T MRI sites is that the across-session test–retest reproducibility/variability obtained with the protocol used
Acknowledgments
Pharmacog is funded by the EU-FP7 for the Innovative Medicine Initiative (grant no. 115009). All members of the Pharmacog project deserve sincere acknowledgement for their significant efforts, but unfortunately, they are too numerous to mention. The authors would like to especially thank the people who contributed to the early phases of this study, including Luca Venturi, Genoveffa Borsci, Thomas Günther, and Aurélien Monnet, as well as Alberto Redolfi for his support with the Intellimaker
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