Measuring cortical mean diffusivity to assess early microstructural cortical change in presymptomatic familial Alzheimer's disease.

BACKGROUND: There is increasing interest in improving understanding of the timing and nature of early neurodegeneration in Alzheimer's disease (AD) and developing methods to measure this in vivo. Autosomal dominant familial Alzheimer's disease (FAD) provides the opportunity for investigation of presymptomatic change. We assessed early microstructural breakdown of cortical grey matter in FAD with diffusion-weighted MRI. METHODS: Diffusion-weighted and T1-weighed MRI were acquired in 38 FAD mutation carriers (17 symptomatic, 21 presymptomatic) and 39 controls. Mean diffusivity (MD) was calculated for six cortical regions previously identified as being particularly vulnerable to FAD-related neurodegeneration. Linear regression compared MD between symptomatic and presymptomatic carriers and controls, adjusting for age and sex. Spearman coefficients assessed associations between cortical MD and cortical thickness. Spearman coefficients also assessed associations between cortical MD and estimated years to/from onset (EYO). Across mutation carriers, linear regression assessed associations between MD and EYO, adjusting for cortical thickness. RESULTS: Compared with controls, cortical MD was higher in symptomatic mutation carriers (mean ± SD CDR = 0.88 ± 0.39) for all six regions (p < 0.001). In late presymptomatic carriers (within 8.1 years of predicted symptom onset), MD was higher in the precuneus (p = 0.04) and inferior parietal cortex (p = 0.003) compared with controls. Across all presymptomatic carriers, MD in the precuneus correlated with EYO (p = 0.04). Across all mutation carriers, there was strong evidence (p < 0.001) of association between MD and cortical thickness in all regions except entorhinal cortex. After adjusting for cortical thickness, there remained an association (p < 0.05) in mutation carriers between MD and EYO in all regions except entorhinal cortex. CONCLUSIONS: Cortical MD measurement detects microstructural breakdown in presymptomatic FAD and correlates with proximity to symptom onset independently of cortical thickness. Cortical MD may thus be a feasible biomarker of early AD-related neurodegeneration, offering additional/complementary information to conventional MRI measures.

Estimation of Large Motion in Lung CT by Integrating Regularized Keypoint Correspondences into Dense Deformable Registration.

We present a novel algorithm for the registration of pulmonary CT scans. Our method is designed for large respiratory motion by integrating sparse keypoint correspondences into a dense continuous optimization framework. The detection of keypoint correspondences enables robustness against large deformations by jointly optimizing over a large number of potential discrete displacements, whereas the dense continuous registration achieves subvoxel alignment with smooth transformations. Both steps are driven by the same normalized gradient fields data term. We employ curvature regularization and a volume change control mechanism to prevent foldings of the deformation grid and restrict the determinant of the Jacobian to physiologically meaningful values. Keypoint correspondences are integrated into the dense registration by a quadratic penalty with adaptively determined weight. Using a parallel matrix-free derivative calculation scheme, a runtime of about 5 min was realized on a standard PC. The proposed algorithm ranks first in the EMPIRE10 challenge on pulmonary image registration. Moreover, it achieves an average landmark distance of 0.82 mm on the DIR-Lab COPD database, thereby improving upon the state of the art in accuracy by 15%. Our algorithm is the first to reach the inter-observer variability in landmark annotation on this dataset.

Multimodal Image Analysis in Alzheimer's Disease via Statistical Modelling of Non-local Intensity Correlations.

The joint analysis of brain atrophy measured with magnetic resonance imaging (MRI) and hypometabolism measured with positron emission tomography with fluorodeoxyglucose (FDG-PET) is of primary importance in developing models of pathological changes in Alzheimer's disease (AD). Most of the current multimodal analyses in AD assume a local (spatially overlapping) relationship between MR and FDG-PET intensities. However, it is well known that atrophy and hypometabolism are prominent in different anatomical areas. The aim of this work is to describe the relationship between atrophy and hypometabolism by means of a data-driven statistical model of non-overlapping intensity correlations. For this purpose, FDG-PET and MRI signals are jointly analyzed through a computationally tractable formulation of partial least squares regression (PLSR). The PLSR model is estimated and validated on a large clinical cohort of 1049 individuals from the ADNI dataset. Results show that the proposed non-local analysis outperforms classical local approaches in terms of predictive accuracy while providing a plausible description of disease dynamics: early AD is characterised by non-overlapping temporal atrophy and temporo-parietal hypometabolism, while the later disease stages show overlapping brain atrophy and hypometabolism spread in temporal, parietal and cortical areas.

Deformable image registration by combining uncertainty estimates from supervoxel belief propagation.

Discrete optimisation strategies have a number of advantages over their continuous counterparts for deformable registration of medical images. For example: it is not necessary to compute derivatives of the similarity term; dense sampling of the search space reduces the risk of becoming trapped in local optima; and (in principle) an optimum can be found without resorting to iterative coarse-to-fine warping strategies. However, the large complexity of high-dimensional medical data renders a direct voxel-wise estimation of deformation vectors impractical. For this reason, previous work on medical image registration using graphical models has largely relied on using a parameterised deformation model and on the use of iterative coarse-to-fine optimisation schemes. In this paper, we propose an approach that enables accurate voxel-wise deformable registration of high-resolution 3D images without the need for intermediate image warping or a multi-resolution scheme. This is achieved by representing the image domain as multiple comprehensive supervoxel layers and making use of the full marginal distribution of all probable displacement vectors after inferring regularity of the deformations using belief propagation. The optimisation acts on the coarse scale representation of supervoxels, which provides sufficient spatial context and is robust to noise in low contrast areas. Minimum spanning trees, which connect neighbouring supervoxels, are employed to model pair-wise deformation dependencies. The optimal displacement for each voxel is calculated by considering the probabilities for all displacements over all overlapping supervoxel graphs and subsequently seeking the mode of this distribution. We demonstrate the applicability of this concept for two challenging applications: first, for intra-patient motion estimation in lung CT scans; and second, for atlas-based segmentation propagation of MRI brain scans. For lung registration, the voxel-wise mode of displacements is found using the mean-shift algorithm, which enables us to determine continuous valued sub-voxel motion vectors. Finding the mode of brain segmentation labels is performed using a voxel-wise majority voting weighted by the displacement uncertainty estimates. Our experimental results show significant improvements in registration accuracy when using the additional information provided by the registration uncertainty estimates. The multi-layer approach enables fusion of multiple complementary proposals, extending the popular fusion approaches from multi-image registration to probabilistic one-to-one image registration.

White matter tract signatures of impaired social cognition in frontotemporal lobar degeneration.

Impairments of social cognition are often leading features in frontotemporal lobar degeneration (FTLD) and likely to reflect large-scale brain network disintegration. However, the neuroanatomical basis of impaired social cognition in FTLD and the role of white matter connections have not been defined. Here we assessed social cognition in a cohort of patients representing two core syndromes of FTLD, behavioural variant frontotemporal dementia (bvFTD; n = 29) and semantic variant primary progressive aphasia (svPPA; n = 15), relative to healthy older individuals (n = 37) using two components of the Awareness of Social Inference Test, canonical emotion identification and sarcasm identification. Diffusion tensor imaging (DTI) was used to derive white matter tract correlates of social cognition performance and compared with the distribution of grey matter atrophy on voxel-based morphometry. The bvFTD and svPPA groups showed comparably severe deficits for identification of canonical emotions and sarcasm, and these deficits were correlated with distributed and overlapping white matter tract alterations particularly affecting frontotemporal connections in the right cerebral hemisphere. The most robust DTI associations were identified in white matter tracts linking cognitive and evaluative processing with emotional responses: anterior thalamic radiation, fornix (emotion identification) and uncinate fasciculus (sarcasm identification). DTI associations of impaired social cognition were more consistent than corresponding grey matter associations. These findings delineate a brain network substrate for the social impairment that characterises FTLD syndromes. The findings further suggest that DTI can generate sensitive and functionally relevant indexes of white matter damage in FTLD, with potential to transcend conventional syndrome boundaries.

Diffusion imaging changes in grey matter in Alzheimer's disease: a potential marker of early neurodegeneration.

Alzheimer's disease (AD) is recognized to have a long presymptomatic period, during which there is progressive accumulation of molecular pathology, followed by inexorable neuronal damage. The ability to identify presymptomatic individuals with evidence of neurodegenerative change, to stage their disease, and to track progressive changes will be important for early diagnosis and for prevention trials. Despite recent advances, particularly in magnetic resonance imaging, our ability to identify early neurodegenerative changes reliably is limited. The development of diffusion-weighted magnetic resonance imaging, which is sensitive to microstructural changes not visible with conventional volumetric techniques, has led to a number of diffusion imaging studies in AD; these have largely focused on white matter changes. However, in AD cerebral grey matter is affected very early, with pathological studies suggesting that grey matter changes predate those in white matter. In this article we review the growing number of studies that assess grey matter diffusivity changes in AD. Although use of the technique is still at a relatively early stage, results so far have been promising. Initial studies identified changes in diffusion measures in the hippocampi of patients with mild cognitive impairment, which predated macroscopic volume loss, with positive predictive value for progression to AD dementia. More recent studies have identified abnormalities in multiple neocortical areas (particularly the posterior cingulate) at various stages of disease progression. Studies of patients who carry genetic mutations predisposing to autosomal dominant familial AD have shown cortical and subcortical grey matter diffusivity changes several years before the expected onset of the first clinical symptoms. The technique is not without potential methodological difficulties, especially relating to partial volume effects, although recent advances appear to be reducing such issues. Going forward, further utilization of grey matter diffusion measurements in AD may improve our understanding with regards to the timing and nature of the earliest presymptomatic neurodegenerative changes. This imaging technique may also be useful in comparing and contrasting subtle variations in different disease subgroups, and as a sensitive outcome measure for presymptomatic clinical trials in AD and other neurodegenerative diseases.

Longitudinal diffusion tensor imaging in frontotemporal dementia.

OBJECTIVE: Novel biomarkers for monitoring progression in neurodegenerative conditions are needed. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. Here we report trajectories of WM change using serial DTI in a cohort with behavioral variant frontotemporal dementia (bvFTD). METHODS: Twenty-three patients with bvFTD (12 having genetic mutations), and 18 age-matched control participants were assessed using DTI and neuropsychological batteries at baseline and ~1.3 years later. Baseline and follow-up DTI scans were registered using a groupwise approach. Annualized rates of change for DTI metrics, neuropsychological measures, and whole brain volume were calculated. DTI metric performances were compared, and sample sizes for potential clinical trials were calculated. RESULTS: In the bvFTD group as a whole, rates of change in fractional anisotropy (FA) and mean diffusivity (MD) within the right paracallosal cingulum were greatest (FA: -6.8%/yr, p < 0.001; MD: 2.9%/yr, p = 0.01). MAPT carriers had the greatest change within left uncinate fasciculus (FA: -7.9%/yr, p < 0.001; MD: 10.9%/yr, p < 0.001); sporadic bvFTD and C9ORF72 carriers had the greatest change within right paracallosal cingulum (sporadic bvFTD, FA: -6.7%/yr, p < 0.001; MD: 3.8%/yr, p = 0.001; C9ORF72, FA: -6.8%/yr, p = 0.004). Sample size estimates using FA change were substantially lower than neuropsychological or whole brain measures of change. INTERPRETATION: Serial DTI scans may be useful for measuring disease progression in bvFTD, with particular trajectories of WM damage emerging. Sample size calculations suggest that longitudinal DTI may be a useful biomarker in future clinical trials.

Simulating neurodegeneration through longitudinal population analysis of structural and diffusion weighted MRI data.

Neuroimaging biomarkers play a prominent role for disease diagnosis or tracking neurodegenerative processes. Multiple methods have been proposed by the community to extract robust disease specific markers from various imaging modalities. Evaluating the accuracy and robustness of developed methods is difficult due to the lack of a biologically realistic ground truth. We propose a proof-of-concept method for a patient- and disease-specific brain neurodegeneration simulator. The proposed scheme, based on longitudinal multi-modal data, has been applied to a population of normal controls and patients diagnosed with Alzheimer's disease or frontotemporal dementia. We simulated follow-up images from baseline scans and compared them to real repeat images. Additionally, simulated maps of volume change are generated, which can be compared to maps estimated from real longitudinal data. The results indicate that the proposed simulator reproduces realistic patient-specific patterns of longitudinal brain change for the given populations.

Ensemble learning incorporating uncertain registration.

This paper proposes a novel approach for improving the accuracy of statistical prediction methods in spatially normalized analysis. This is achieved by incorporating registration uncertainty into an ensemble learning scheme. A probabilistic registration method is used to estimate a distribution of probable mappings between subject and atlas space. This allows the estimation of the distribution of spatially normalized feature data, e.g., grey matter probability maps. From this distribution, samples are drawn for use as training examples. This allows the creation of multiple predictors, which are subsequently combined using an ensemble learning approach. Furthermore, extra testing samples can be generated to measure the uncertainty of prediction. This is applied to separating subjects with Alzheimer's disease from normal controls using a linear support vector machine on a region of interest in magnetic resonance images of the brain. We show that our proposed method leads to an improvement in discrimination using voxel-based morphometry and deformation tensor-based morphometry over bootstrap aggregating, a common ensemble learning framework. The proposed approach also generates more reasonable soft-classification predictions than bootstrap aggregating. We expect that this approach could be applied to other statistical prediction tasks where registration is important.

A Bayesian approach for spatially adaptive regularisation in non-rigid registration.

This paper introduces a novel method for inferring spatially varying regularisation in non-rigid registration. This is achieved through full Bayesian inference on a probabilistic registration model, where the prior on transformations is parametrised as a weighted mixture of spatially localised components. Such an approach has the advantage of allowing the registration to be more flexibly driven by the data than a more traditional global regularisation scheme, such as bending energy. The proposed method adaptively determines the influence of the prior in a local region. The importance of the prior may be reduced in areas where the data better supports deformations, or can enforce a stronger constraint in less informative areas. Consequently, the use of such a spatially adaptive prior may reduce the unwanted impact of regularisation on the inferred deformation field. This is especially important for applications such as tensor based morphometry, where the features of interest are directly derived from the deformation field. The proposed approach is demonstrated with application to tensor based morphometry analysis of subjects with Alzheimer's disease and healthy controls. The results show that using the proposed spatially adaptive prior leads to deformation fields that have a substantially lower average complexity, but which also provide more accurate localisation of statistical group differences.

Probabilistic inference of regularisation in non-rigid registration.

A long-standing issue in non-rigid image registration is the choice of the level of regularisation. Regularisation is necessary to preserve the smoothness of the registration and penalise against unnecessary complexity. The vast majority of existing registration methods use a fixed level of regularisation, which is typically hand-tuned by a user to provide "nice" results. However, the optimal level of regularisation will depend on the data which is being processed; lower signal-to-noise ratios require higher regularisation to avoid registering image noise as well as features, and different pairs of images require registrations of varying complexity depending on their anatomical similarity. In this paper we present a probabilistic registration framework that infers the level of regularisation from the data. An additional benefit of this proposed probabilistic framework is that estimates of the registration uncertainty are obtained. This framework has been implemented using a free-form deformation transformation model, although it would be generically applicable to a range of transformation models. We demonstrate our registration framework on the application of inter-subject brain registration of healthy control subjects from the NIREP database. In our results we show that our framework appropriately adapts the level of regularisation in the presence of noise, and that inferring regularisation on an individual basis leads to a reduction in model over-fitting as measured by image folding while providing a similar level of overlap.

Longitudinal brain MRI analysis with uncertain registration.

In this paper we propose a novel approach for incorporating measures of spatial uncertainty, which are derived from non-rigid registration, into spatially normalised statistics. Current approaches to spatially normalised statistical analysis use point-estimates of the registration parameters. This is limiting as the registration will rarely be completely accurate, and therefore data smoothing is often used to compensate for the uncertainty of the mapping. We derive localised measurements of spatial uncertainty from a probabilistic registration framework, which provides a principled approach to image smoothing. We evaluate our method using longitudinal deformation features from a set of MR brain images acquired from the Alzheimer's Disease Neuroimaging Initiative. These images are spatially normalised using our probabilistic registration algorithm. The spatially normalised longitudinal features are adaptively smoothed according to the registration uncertainty. The proposed adaptive smoothing shows improved classification results, (84% correct Alzheimer's Disease vs. controls), over either not smoothing (79.6%), or using a Gaussian filter with sigma = 2mm (78.8%).