The present study is the first longitudinal study to directly demonstrate the association between acute FLAIR hyper-intensity lesion and post-traumatic atrophy. We excluded patients who suffered large or medium focal lesions including contusions, extra- or intra- axial hematomas from the present study in order to focus on the relationship between diffuse injury, particularly DAIs, and cerebral atrophy after TBI. DAIs can be visualized indirectly through shear hemorrhages caused by tearing lesions of blood vessels (Scheid et al., 2003
; Tong et al., 2003
) or more directly by analyzing white matter hyperintensities on FLAIR MRI (Marquez de la Plata et al., 2007
; Pierallini et al., 2000
; Takaoka et al., 2002
). We found that acute hyperintensity FLAIR lesions are strongly predictive of post-traumatic cerebral atrophy. Although the pathophysiology of the post-TBI cerebral atrophy remains unknown, axonal injury and subsequent Wallerian degeneration may be a possible mechanism. The current working hypothesis, based on animal data (Povlishock et al., 2005
; Smith et al., 2003
), is that at the acute stage (hours to days after non-penetrating brain injury), the axons swell due to the local ionic homeostatic disruption, increased permeability of the axolemma, with immediate mechanical damage to the axonal cytoskeleton (primary axotomy) seen in severe cases. Days to months after the injury, pathological changes of DAI are believed to consist of progressive disorganization of the axonal cytoskeleton and progressive protein accumulation, leading to disconnection of axons (secondary axotomy). The primary and secondary axotomy also triggers the local or even global metabolic changes which would lead to further cell death and Wallerian degeneration (Smith et al., 2003
). This pathologic process may lead to cerebral atrophy in the chronic phase after TBI. Our data is consistent with this working hypothesis, and also indicates that tracking of macroscopic lesions visible in FLAIR scans may be a useful method to monitor progressive tissue pathology associated with DAI.
The current study confirmed our prior finding that acute hyperintensity FLAIR lesion was an important factor for predicting functional outcome, though only moderately correlated with FSE (Marquez de la Plata et al., 2007
). Combined with GCS in the ER and age, the acute DAI lesion volume could be used to stratify injury severity when selecting patients for TBI clinical trials. Our study indicates that the follow-up MRI, especially on high magnetic field, could offer useful information on the pathological change of DAI, which would be potentially useful in DAI-directed therapies.
While FLAIR is a commonly used clinical sequence which all physicians are familiar with, it may not be the most sensitive MR sequence to detect DAI. Several other MR techniques have been proposed to increase the sensitivity of detecting DAI in vivo
. T2-weighted gradient echo is excellent in detecting acute small punctuate hemorrhagic lesions. The number of traumatic microbleeds detected on T2-weighted gradient echo sequence at chronic stage (≥3 months after TBI) correlated significantly with GCS, but not with long-term outcome measured by GOS-E (Pierallini et al., 2000
; Scheid et al., 2003
). A new high-resolution 3D gradient-echo MR imaging technique, known as susceptibility-weighted imaging (SWI) is much more sensitive than conventional T2-weighted gradient-echo sequences in detecting hemorrhagic DAI. Number of traumatic microhemmorhagic lesion detected by SWI correlated better with GOS-E than that detected by gradient echo (Tong et al., 2003
). No longitudinal data is available to assess whether SWI lesions correlate with post-traumatic brain atrophy. Diffusion-weighted imaging (DWI) has proven to be highly sensitive for the detection of early cytotoxic edema in the setting of acute stroke. DWI has not been widely used in clinical TBI, though the sensitivity of DWI to identify DAI lesions is similar to that of FLAIR. It is less sensitive than T2 gradient echo for detecting hemorrhagic lesions (Huisman, 2002
; Huisman et al., 2003
; Kinoshita et al., 2005
). The volume of DWI lesions in white matter is moderately correlated with functional outcome (Ayala et al., 2008
). Unlike conventional DWI, diffusion tensor imaging (DTI) characterizes the diffusion of water along white matter tracts. Our group and others are studying DTI in the hope that it would be more sensitive to axonal pathology after traumatic injury (Bazarian et al., 2007
; Kim et al., 2008
; Sidaros et al., 2008
; Wang et al., 2008
). DTI is able to visualize changes that were not seen on conventional scans and strongly correlated with functional outcome. However the analysis of DTI data is time-consuming, experience-dependent and may not be ideally suitable for routine clinical practice. Overall, the combination of FLAIR and other MRI sequences may provide additional information about injury severity and correlate with the functional outcome better.
Our findings of reduced WBV, WMV, and GMV at approximately 8 months after TBI are consistent with previous volumetric studies (MacKenzie et al., 2002
; Trivedi et al., 2007
). This indicated that our method of brain volume measurement is reliable and consistent. In our study, SIENAX, a fully automated method, has been used to measure atrophy. This program has been shown to be an accurate approach to measure cross-sectional normalized brain volume with 0.5–1% brain volume accuracy for a single-time point. It has successfully coped with both de-skulling and tissue segmentation, and can be used for the subjects with extreme parenchymal loss (Smith et al., 2002
). Recently, its reliability has be demonstrated in other neurological conditions, such as multiple sclerosis (MS) and Alzheimer's disease (Anderson et al., 2006
; Smith et al., 2007
). A particular advantage of SIENAX is that it is relatively insensitive to different scanning parameters. For MS-related brain atrophy, the inter-center agreement assessed with the concordance correlation coefficient was 0.94 between two centers regardless of the difference of magnetic field strength and scanning parameters (Jasperse et al., 2007
). SIENA is a similar fully automated program developed to measure longitudinal atrophy rate. Our finding of cerebral atrophy measured using SIENAX was commensurate to the results of Trivedi et al. (2007
) using SIENA. The development of SIENA/SIENAX makes it practical to use atrophy rate/state as an index of disease progression in clinical studies.
The present investigation was a pilot study, and a larger scale investigation is under way in our group to confirm these pilot results. While many initial scans took place within the first week, many occurred several days after injury. The heterogeneity in the interval from injury to first scan may confound results, as it is possible that FLAIR lesions increase in conspicuity over time. In order to establish the utility of MRI as a biomarker in clinical trials, scans obtained within 24
h of injury must be studied. Furthermore, neuropathologic studies are needed to correlate the cellular and tissue abnormalities with lesions detected by MRI.
The present study provides in vivo evidence of pathological change of DAI after TBI. It demonstrates a strong association between post-traumatic cerebral atrophy and DAI. The strategy presented in this study could be a practical method to monitor the efficacy of DAI-directed therapies in future clinical trials.