Assessment of a deep-learning system for fracture detection in musculoskeletal radiographs.

Missed fractures are the most common diagnostic error in emergency departments and can lead to treatment delays and long-term disability. Here we show through a multi-site study that a deep-learning system can accurately identify fractures throughout the adult musculoskeletal system. This approach may have the potential to reduce future diagnostic errors in radiograph interpretation.

Volume Change in Frontal Cholinergic Structures After Traumatic Brain Injury and Cognitive Outcome.

The cholinergic nuclei in the basal forebrain innervate frontal cortical structures regulating attention. Our aim was to investigate if cognitive test results measuring attention relate to the longitudinal volume change of cholinergically innervated structures following traumatic brain injury (TBI). During the prospective, observational TBIcare project patients with all severities of TBI (n = 114) and controls with acute orthopedic injuries (n = 17) were recruited. Head MRI was obtained in both acute (mean 2 weeks post-injury) and late (mean 8 months) time points. T1-weighted 3D MR images were analyzed with an automatic segmentation method to evaluate longitudinal, structural brain volume change. The cognitive outcome was assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB). Analyses included 16 frontal cortical structures, of which four showed a significant correlation between post-traumatic volume change and the CANTAB test results. The strongest correlation was found between the volume loss of the supplementary motor cortex and motor screening task results (R-sq 0.16, p < 0.0001), where poorer test results correlated with greater atrophy. Of the measured sum structures, greater cortical gray matter atrophy rate showed a significant correlation with the poorer CANTAB test results. TBI caused volume loss of frontal cortical structures that are heavily innervated by cholinergic neurons is associated with neuropsychological test results measuring attention.

Integrative Analysis of Circulating Metabolite Profiles and Magnetic Resonance Imaging Metrics in Patients with Traumatic Brain Injury.

Recent evidence suggests that patients with traumatic brain injuries (TBIs) have a distinct circulating metabolic profile. However, it is unclear if this metabolomic profile corresponds to changes in brain morphology as observed by magnetic resonance imaging (MRI). The aim of this study was to explore how circulating serum metabolites, following TBI, relate to structural MRI (sMRI) findings. Serum samples were collected upon admission to the emergency department from patients suffering from acute TBI and metabolites were measured using mass spectrometry-based metabolomics. Most of these patients sustained a mild TBI. In the same patients, sMRIs were taken and volumetric data were extracted (138 metrics). From a pool of 203 eligible screened patients, 96 met the inclusion criteria for this study. Metabolites were summarized as eight clusters and sMRI data were reduced to 15 independent components (ICs). Partial correlation analysis showed that four metabolite clusters had significant associations with specific ICs, reflecting both the grey and white matter brain injury. Multiple machine learning approaches were then applied in order to investigate if circulating metabolites could distinguish between positive and negative sMRI findings. A logistic regression model was developed, comprised of two metabolic predictors (erythronic acid and myo-inositol), which, together with neurofilament light polypeptide (NF-L), discriminated positive and negative sMRI findings with an area under the curve of the receiver-operating characteristic of 0.85 (specificity = 0.89, sensitivity = 0.65). The results of this study show that metabolomic analysis of blood samples upon admission, either alone or in combination with protein biomarkers, can provide valuable information about the impact of TBI on brain structural changes.

Explainable Anatomical Shape Analysis Through Deep Hierarchical Generative Models.

Quantification of anatomical shape changes currently relies on scalar global indexes which are largely insensitive to regional or asymmetric modifications. Accurate assessment of pathology-driven anatomical remodeling is a crucial step for the diagnosis and treatment of many conditions. Deep learning approaches have recently achieved wide success in the analysis of medical images, but they lack interpretability in the feature extraction and decision processes. In this work, we propose a new interpretable deep learning model for shape analysis. In particular, we exploit deep generative networks to model a population of anatomical segmentations through a hierarchy of conditional latent variables. At the highest level of this hierarchy, a two-dimensional latent space is simultaneously optimised to discriminate distinct clinical conditions, enabling the direct visualisation of the classification space. Moreover, the anatomical variability encoded by this discriminative latent space can be visualised in the segmentation space thanks to the generative properties of the model, making the classification task transparent. This approach yielded high accuracy in the categorisation of healthy and remodelled left ventricles when tested on unseen segmentations from our own multi-centre dataset as well as in an external validation set, and on hippocampi from healthy controls and patients with Alzheimer's disease when tested on ADNI data. More importantly, it enabled the visualisation in three-dimensions of both global and regional anatomical features which better discriminate between the conditions under exam. The proposed approach scales effectively to large populations, facilitating high-throughput analysis of normal anatomy and pathology in large-scale studies of volumetric imaging.

Quantitative assessment of myelination patterns in preterm neonates using T2-weighted MRI.

Myelination is considered to be an important developmental process during human brain maturation and closely correlated with gestational age. Quantitative assessment of the myelination status requires dedicated imaging, but the conventional T2-weighted scans routinely acquired during clinical imaging of neonates carry signatures that are thought to be associated with myelination. In this work, we develop a quatitative marker of progressing myelination for assessment preterm neonatal brain maturation based on novel automatic segmentation method for myelin-like signals on T2-weighted magnetic resonance images. Firstly we define a segmentation protocol for myelin-like signals. We then develop an expectation-maximization framework to obtain the automatic segmentations of myelin-like signals with explicit class for partial volume voxels whose locations are configured in relation to the composing pure tissues via second-order Markov random fields. The proposed segmentation achieves high Dice overlaps of 0.83 with manual annotations. The automatic segmentations are then used to track volumes of myelinated tissues in the regions of the central brain structures and brainstem. Finally, we construct a spatio-temporal growth models for myelin-like signals, which allows us to predict gestational age at scan in preterm infants with root mean squared error 1.41 weeks.

Structural brain imaging in Alzheimer's disease and mild cognitive impairment: biomarker analysis and shared morphometry database.

Magnetic resonance (MR) imaging is a powerful technique for non-invasive in-vivo imaging of the human brain. We employed a recently validated method for robust cross-sectional and longitudinal segmentation of MR brain images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Specifically, we segmented 5074 MR brain images into 138 anatomical regions and extracted time-point specific structural volumes and volume change during follow-up intervals of 12 or 24 months. We assessed the extracted biomarkers by determining their power to predict diagnostic classification and by comparing atrophy rates to published meta-studies. The approach enables comprehensive analysis of structural changes within the whole brain. The discriminative power of individual biomarkers (volumes/atrophy rates) is on par with results published by other groups. We publish all quality-checked brain masks, structural segmentations, and extracted biomarkers along with this article. We further share the methodology for brain extraction (pincram) and segmentation (MALPEM, MALPEM4D) as open source projects with the community. The identified biomarkers hold great potential for deeper analysis, and the validated methodology can readily be applied to other imaging cohorts.

Data-Driven Differential Diagnosis of Dementia Using Multiclass Disease State Index Classifier.

Clinical decision support systems (CDSSs) hold potential for the differential diagnosis of neurodegenerative diseases. We developed a novel CDSS, the PredictND tool, designed for differential diagnosis of different types of dementia. It combines information obtained from multiple diagnostic tests such as neuropsychological tests, MRI and cerebrospinal fluid samples. Here we evaluated how the classifier used in it performs in differentiating between controls with subjective cognitive decline, dementia due to Alzheimer's disease, vascular dementia, frontotemporal lobar degeneration and dementia with Lewy bodies. We used the multiclass Disease State Index classifier, which is the classifier used by the PredictND tool, to differentiate between controls and patients with the four different types of dementia. The multiclass Disease State Index classifier is an extension of a previously developed two-class Disease State Index classifier. As the two-class Disease State Index classifier, the multiclass Disease State Index classifier also offers a visualization of its decision making process, which makes it especially suitable for medical decision support where interpretability of the results is highly important. A subset of the Amsterdam Dementia cohort, consisting of 504 patients (age 65 ± 8 years, 44% females) with data from neuropsychological tests, cerebrospinal fluid samples and both automatic and visual MRI quantifications, was used for the evaluation. The Disease State Index classifier was highly accurate in separating the five classes from each other (balanced accuracy 82.3%). Accuracy was highest for vascular dementia and lowest for dementia with Lewy bodies. For the 50% of patients for which the classifier was most confident on the classification the balanced accuracy was 93.6%. Data-driven CDSSs can be of aid in differential diagnosis in clinical practice. The decision support system tested in this study was highly accurate in separating the different dementias and controls from each other. In addition to the predicted class, it also provides a confidence measure for the classification.

Regional brain morphometry in patients with traumatic brain injury based on acute- and chronic-phase magnetic resonance imaging.

Traumatic brain injury (TBI) is caused by a sudden external force and can be very heterogeneous in its manifestation. In this work, we analyse T1-weighted magnetic resonance (MR) brain images that were prospectively acquired from patients who sustained mild to severe TBI. We investigate the potential of a recently proposed automatic segmentation method to support the outcome prediction of TBI. Specifically, we extract meaningful cross-sectional and longitudinal measurements from acute- and chronic-phase MR images. We calculate regional volume and asymmetry features at the acute/subacute stage of the injury (median: 19 days after injury), to predict the disability outcome of 67 patients at the chronic disease stage (median: 229 days after injury). Our results indicate that small structural volumes in the acute stage (e.g. of the hippocampus, accumbens, amygdala) can be strong predictors for unfavourable disease outcome. Further, group differences in atrophy are investigated. We find that patients with unfavourable outcome show increased atrophy. Among patients with severe disability outcome we observed a significantly higher mean reduction of cerebral white matter (3.1%) as compared to patients with low disability outcome (0.7%).

Five-class differential diagnostics of neurodegenerative diseases using random undersampling boosting.

Differentiating between different types of neurodegenerative diseases is not only crucial in clinical practice when treatment decisions have to be made, but also has a significant potential for the enrichment of clinical trials. The purpose of this study is to develop a classification framework for distinguishing the four most common neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobe degeneration, Dementia with Lewy bodies and vascular dementia, as well as patients with subjective memory complaints. Different biomarkers including features from images (volume features, region-wise grading features) and non-imaging features (CSF measures) were extracted for each subject. In clinical practice, the prevalence of different dementia types is imbalanced, posing challenges for learning an effective classification model. Therefore, we propose the use of the RUSBoost algorithm in order to train classifiers and to handle the class imbalance training problem. Furthermore, a multi-class feature selection method based on sparsity is integrated into the proposed framework to improve the classification performance. It also provides a way for investigating the importance of different features and regions. Using a dataset of 500 subjects, the proposed framework achieved a high accuracy of 75.2% with a balanced accuracy of 69.3% for the five-class classification using ten-fold cross validation, which is significantly better than the results using support vector machine or random forest, demonstrating the feasibility of the proposed framework to support clinical decision making.

A Novel Grading Biomarker for the Prediction of Conversion From Mild Cognitive Impairment to Alzheimer's Disease.

OBJECTIVE: Identifying mild cognitive impairment (MCI) subjects who will progress to Alzheimer's disease (AD) is not only crucial in clinical practice, but also has a significant potential to enrich clinical trials. The purpose of this study is to develop an effective biomarker for an accurate prediction of MCI-to-AD conversion from magnetic resonance images. METHODS: We propose a novel grading biomarker for the prediction of MCI-to-AD conversion. First, we comprehensively study the effects of several important factors on the performance in the prediction task including registration accuracy, age correction, feature selection, and the selection of training data. Based on the studies of these factors, a grading biomarker is then calculated for each MCI subject using sparse representation techniques. Finally, the grading biomarker is combined with age and cognitive measures to provide a more accurate prediction of MCI-to-AD conversion. RESULTS: Using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, the proposed global grading biomarker achieved an area under the receiver operating characteristic curve (AUC) in the range of 79-81% for the prediction of MCI-to-AD conversion within three years in tenfold cross validations. The classification AUC further increases to 84-92% when age and cognitive measures are combined with the proposed grading biomarker. CONCLUSION: The obtained accuracy of the proposed biomarker benefits from the contributions of different factors: a tradeoff registration level to align images to the template space, the removal of the normal aging effect, selection of discriminative voxels, the calculation of the grading biomarker using AD and normal control groups, and the integration of sparse representation technique and the combination of cognitive measures. SIGNIFICANCE: The evaluation on the ADNI dataset shows the efficacy of the proposed biomarker and demonstrates a significant contribution in accurate prediction of MCI-to-AD conversion.

Efficient multi-scale 3D CNN with fully connected CRF for accurate brain lesion segmentation.

We propose a dual pathway, 11-layers deep, three-dimensional Convolutional Neural Network for the challenging task of brain lesion segmentation. The devised architecture is the result of an in-depth analysis of the limitations of current networks proposed for similar applications. To overcome the computational burden of processing 3D medical scans, we have devised an efficient and effective dense training scheme which joins the processing of adjacent image patches into one pass through the network while automatically adapting to the inherent class imbalance present in the data. Further, we analyze the development of deeper, thus more discriminative 3D CNNs. In order to incorporate both local and larger contextual information, we employ a dual pathway architecture that processes the input images at multiple scales simultaneously. For post-processing of the network's soft segmentation, we use a 3D fully connected Conditional Random Field which effectively removes false positives. Our pipeline is extensively evaluated on three challenging tasks of lesion segmentation in multi-channel MRI patient data with traumatic brain injuries, brain tumours, and ischemic stroke. We improve on the state-of-the-art for all three applications, with top ranking performance on the public benchmarks BRATS 2015 and ISLES 2015. Our method is computationally efficient, which allows its adoption in a variety of research and clinical settings. The source code of our implementation is made publicly available.

ISLES 2015 - A public evaluation benchmark for ischemic stroke lesion segmentation from multispectral MRI.

Ischemic stroke is the most common cerebrovascular disease, and its diagnosis, treatment, and study relies on non-invasive imaging. Algorithms for stroke lesion segmentation from magnetic resonance imaging (MRI) volumes are intensely researched, but the reported results are largely incomparable due to different datasets and evaluation schemes. We approached this urgent problem of comparability with the Ischemic Stroke Lesion Segmentation (ISLES) challenge organized in conjunction with the MICCAI 2015 conference. In this paper we propose a common evaluation framework, describe the publicly available datasets, and present the results of the two sub-challenges: Sub-Acute Stroke Lesion Segmentation (SISS) and Stroke Perfusion Estimation (SPES). A total of 16 research groups participated with a wide range of state-of-the-art automatic segmentation algorithms. A thorough analysis of the obtained data enables a critical evaluation of the current state-of-the-art, recommendations for further developments, and the identification of remaining challenges. The segmentation of acute perfusion lesions addressed in SPES was found to be feasible. However, algorithms applied to sub-acute lesion segmentation in SISS still lack accuracy. Overall, no algorithmic characteristic of any method was found to perform superior to the others. Instead, the characteristics of stroke lesion appearances, their evolution, and the observed challenges should be studied in detail. The annotated ISLES image datasets continue to be publicly available through an online evaluation system to serve as an ongoing benchmarking resource (www.isles-challenge.org).

Learning Biomarker Models for Progression Estimation of Alzheimer's Disease.

Being able to estimate a patient's progress in the course of Alzheimer's disease and predicting future progression based on a number of observed biomarker values is of great interest for patients, clinicians and researchers alike. In this work, an approach for disease progress estimation is presented. Based on a set of subjects that convert to a more severe disease stage during the study, models that describe typical trajectories of biomarker values in the course of disease are learned using quantile regression. A novel probabilistic method is then derived to estimate the current disease progress as well as the rate of progression of an individual by fitting acquired biomarkers to the models. A particular strength of the method is its ability to naturally handle missing data. This means, it is applicable even if individual biomarker measurements are missing for a subject without requiring a retraining of the model. The functionality of the presented method is demonstrated using synthetic and--employing cognitive scores and image-based biomarkers--real data from the ADNI study. Further, three possible applications for progress estimation are demonstrated to underline the versatility of the approach: classification, construction of a spatio-temporal disease progression atlas and prediction of future disease progression.

Differential diagnosis of neurodegenerative diseases using structural MRI data.

Different neurodegenerative diseases can cause memory disorders and other cognitive impairments. The early detection and the stratification of patients according to the underlying disease are essential for an efficient approach to this healthcare challenge. This emphasizes the importance of differential diagnostics. Most studies compare patients and controls, or Alzheimer's disease with one other type of dementia. Such a bilateral comparison does not resemble clinical practice, where a clinician is faced with a number of different possible types of dementia. Here we studied which features in structural magnetic resonance imaging (MRI) scans could best distinguish four types of dementia, Alzheimer's disease, frontotemporal dementia, vascular dementia, and dementia with Lewy bodies, and control subjects. We extracted an extensive set of features quantifying volumetric and morphometric characteristics from T1 images, and vascular characteristics from FLAIR images. Classification was performed using a multi-class classifier based on Disease State Index methodology. The classifier provided continuous probability indices for each disease to support clinical decision making. A dataset of 504 individuals was used for evaluation. The cross-validated classification accuracy was 70.6% and balanced accuracy was 69.1% for the five disease groups using only automatically determined MRI features. Vascular dementia patients could be detected with high sensitivity (96%) using features from FLAIR images. Controls (sensitivity 82%) and Alzheimer's disease patients (sensitivity 74%) could be accurately classified using T1-based features, whereas the most difficult group was the dementia with Lewy bodies (sensitivity 32%). These results were notable better than the classification accuracies obtained with visual MRI ratings (accuracy 44.6%, balanced accuracy 51.6%). Different quantification methods provided complementary information, and consequently, the best results were obtained by utilizing several quantification methods. The results prove that automatic quantification methods and computerized decision support methods are feasible for clinical practice and provide comprehensive information that may help clinicians in the diagnosis making.

Dynamic Changes in White Matter Abnormalities Correlate With Late Improvement and Deterioration Following TBI: A Diffusion Tensor Imaging Study.

OBJECTIVE: Traumatic brain injury (TBI) is not a single insult with monophasic resolution, but a chronic disease, with dynamic processes that remain active for years. We aimed to assess patient trajectories over the entire disease narrative, from ictus to late outcome. METHODS: Twelve patients with moderate-to-severe TBI underwent magnetic resonance imaging in the acute phase (within 1 week of injury) and twice in the chronic phase of injury (median 7 and 21 months), with some undergoing imaging at up to 2 additional time points. Longitudinal imaging changes were assessed using structural volumetry, deterministic tractography, voxel-based diffusion tensor analysis, and region of interest analyses (including corpus callosum, parasagittal white matter, and thalamus). Imaging changes were related to behavior. RESULTS: Changes in structural volumes, fractional anisotropy, and mean diffusivity continued for months to years postictus. Changes in diffusion tensor imaging were driven by increases in both axial and radial diffusivity except for the earliest time point, and were associated with changes in reaction time and performance in a visual memory and learning task (paired associates learning). Dynamic structural changes after TBI can be detected using diffusion tensor imaging and could explain changes in behavior. CONCLUSIONS: These data can provide further insight into early and late pathophysiology, and begin to provide a framework that allows magnetic resonance imaging to be used as an imaging biomarker of therapy response. Knowledge of the temporal pattern of changes in TBI patient populations also provides a contextual framework for assessing imaging changes in individuals at any given time point.

Multi-stage Biomarker Models for Progression Estimation in Alzheimer's Disease.

The estimation of disease progression in Alzheimer's disease (AD) based on a vector of quantitative biomarkers is of high interest to clinicians, patients, and biomedical researchers alike. In this work, quantile regression is employed to learn statistical models describing the evolution of such biomarkers. Two separate models are constructed using (1) subjects that progress from a cognitively normal (CN) stage to mild cognitive impairment (MCI) and (2) subjects that progress from MCI to AD during the observation window of a longitudinal study. These models are then automatically combined to develop a multi-stage disease progression model for the whole disease course. A probabilistic approach is derived to estimate the current disease progress (DP) and the disease progression rate (DPR) of a given individual by fitting any acquired biomarkers to these models. A particular strength of this method is that it is applicable even if individual biomarker measurements are missing for the subject. Employing cognitive scores and image-based biomarkers, the presented method is used to estimate DP and DPR for subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Further, the potential use of these values as features for different classification tasks is demonstrated. For example, accuracy of 64% is reached for CN vs. MCI vs. AD classification.

Brain Extraction Using Label Propagation and Group Agreement: Pincram.

Accurately delineating the brain on magnetic resonance (MR) images of the head is a prerequisite for many neuroimaging methods. Most existing methods exhibit disadvantages in that they are laborious, yield inconsistent results, and/or require training data to closely match the data to be processed. Here, we present pincram, an automatic, versatile method for accurately labelling the adult brain on T1-weighted 3D MR head images. The method uses an iterative refinement approach to propagate labels from multiple atlases to a given target image using image registration. At each refinement level, a consensus label is generated. At the subsequent level, the search for the brain boundary is constrained to the neighbourhood of the boundary of this consensus label. The method achieves high accuracy (Jaccard coefficient > 0.95 on typical data, corresponding to a Dice similarity coefficient of > 0.97) and performs better than many state-of-the-art methods as evidenced by independent evaluation on the Segmentation Validation Engine. Via a novel self-monitoring feature, the program generates the "success index," a scalar metadatum indicative of the accuracy of the output label. Pincram is available as open source software.

Standardized evaluation of algorithms for computer-aided diagnosis of dementia based on structural MRI: the CADDementia challenge.

Algorithms for computer-aided diagnosis of dementia based on structural MRI have demonstrated high performance in the literature, but are difficult to compare as different data sets and methodology were used for evaluation. In addition, it is unclear how the algorithms would perform on previously unseen data, and thus, how they would perform in clinical practice when there is no real opportunity to adapt the algorithm to the data at hand. To address these comparability, generalizability and clinical applicability issues, we organized a grand challenge that aimed to objectively compare algorithms based on a clinically representative multi-center data set. Using clinical practice as the starting point, the goal was to reproduce the clinical diagnosis. Therefore, we evaluated algorithms for multi-class classification of three diagnostic groups: patients with probable Alzheimer's disease, patients with mild cognitive impairment and healthy controls. The diagnosis based on clinical criteria was used as reference standard, as it was the best available reference despite its known limitations. For evaluation, a previously unseen test set was used consisting of 354 T1-weighted MRI scans with the diagnoses blinded. Fifteen research teams participated with a total of 29 algorithms. The algorithms were trained on a small training set (n=30) and optionally on data from other sources (e.g., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle flagship study of aging). The best performing algorithm yielded an accuracy of 63.0% and an area under the receiver-operating-characteristic curve (AUC) of 78.8%. In general, the best performances were achieved using feature extraction based on voxel-based morphometry or a combination of features that included volume, cortical thickness, shape and intensity. The challenge is open for new submissions via the web-based framework: http://caddementia.grand-challenge.org.

Robust whole-brain segmentation: application to traumatic brain injury.

We propose a framework for the robust and fully-automatic segmentation of magnetic resonance (MR) brain images called "Multi-Atlas Label Propagation with Expectation-Maximisation based refinement" (MALP-EM). The presented approach is based on a robust registration approach (MAPER), highly performant label fusion (joint label fusion) and intensity-based label refinement using EM. We further adapt this framework to be applicable for the segmentation of brain images with gross changes in anatomy. We propose to account for consistent registration errors by relaxing anatomical priors obtained by multi-atlas propagation and a weighting scheme to locally combine anatomical atlas priors and intensity-refined posterior probabilities. The method is evaluated on a benchmark dataset used in a recent MICCAI segmentation challenge. In this context we show that MALP-EM is competitive for the segmentation of MR brain scans of healthy adults when compared to state-of-the-art automatic labelling techniques. To demonstrate the versatility of the proposed approach, we employed MALP-EM to segment 125 MR brain images into 134 regions from subjects who had sustained traumatic brain injury (TBI). We employ a protocol to assess segmentation quality if no manual reference labels are available. Based on this protocol, three independent, blinded raters confirmed on 13 MR brain scans with pathology that MALP-EM is superior to established label fusion techniques. We visually confirm the robustness of our segmentation approach on the full cohort and investigate the potential of derived symmetry-based imaging biomarkers that correlate with and predict clinically relevant variables in TBI such as the Marshall Classification (MC) or Glasgow Outcome Score (GOS). Specifically, we show that we are able to stratify TBI patients with favourable outcomes from non-favourable outcomes with 64.7% accuracy using acute-phase MR images and 66.8% accuracy using follow-up MR images. Furthermore, we are able to differentiate subjects with the presence of a mass lesion or midline shift from those with diffuse brain injury with 76.0% accuracy. The thalamus, putamen, pallidum and hippocampus are particularly affected. Their involvement predicts TBI disease progression.