João M.S. Pereira

Atrophy patterns in histologic vs clinical groupings of frontotemporal lobar degeneration

Objective: Predictable patterns of atrophy are associated with the clinical subtypes of frontotemporal dementia (FTD): behavioral variant (bvFTD), semantic dementia (SEMD), and progressive nonfluent aphasia (PNFA). Some studies of pathologic subtypes have also suggested specific atrophy patterns; however, results are inconsistent. Our aim was to test the hypothesis that clinical, but not pathologic, classification (FTD with ubiquitin inclusions [FTD-U] and FTD with tau inclusions [FTD-T]) is associated with predictable patterns of regional atrophy. Methods: Magnetic resonance scans of nine FTD-U and six FTD-T patients (histologically confirmed) were compared with 25 controls using voxel-based morphometry (VBM). Analyses were conducted with the patient group classified according to histologic or clinical variant. Additionally, three Alzheimer pathology patients who had the syndrome of SEMD in life (FTD-A) were analyzed. Results: The VBM studies in clinical variants confirmed established patterns of atrophy (SEMD, rostral temporal; bvFTD, mesial frontal; PNFA, left insula). FTD-U and FTD-T VBM results were very similar, showing severe atrophy in the temporal poles, mesial frontal lobe, and insulae. A conjunction analysis confirmed this similarity. Subgroup analysis found that SEMD associated with either FTD-T or FTD-U was associated with similar rostral temporal atrophy; however, FTD-A had a qualitatively different pattern of left hippocampal atrophy. Conclusions: While there is predictable atrophy for clinical variants of frontotemporal dementia (FTD), histologic FTD variants show no noticeable differences. Reports of specific atrophy profiles are likely the result of idiosyncrasies in small groups. Semantic dementia associated with Alzheimer pathology, however, presented a distinct atrophy pattern.

The impact of skull-stripping and radio-frequency bias correction on grey-matter segmentation for voxel-based morphometry

This study evaluates the application of (i) skull-stripping methods (hybrid watershed algorithm (HWA), brain surface extractor (BSE) and brain-extraction tool (BET2)) and (ii) bias correction algorithms (nonparametric nonuniform intensity normalisation (N3), bias field corrector (BFC) and FMRIBs automated segmentation tool (FAST)) as pre-processing pipelines for the technique of voxel-based morphometry (VBM) using statistical parametric mapping v.5 (SPM5). The pipelines were evaluated using a BrainWeb phantom, and those that performed consistently were further assessed using artificial-lesion masks applied to 10 healthy controls compared to the original unlesioned scans, and finally, 20 Alzheimers disease (AD) patients versus 23 controls. In each case, pipelines were compared to each other and to those from default SPM5 methodology. The BET2+N3 pipeline was found to produce the least miswarping to template induced by real abnormalities, and performed consistently better than the other methods for the above experiments. Occasionally, the clusters of significant differences located close to the boundary were dragged out of the glass-brain projections -- this could be corrected by adding background noise to low-probability voxels in the grey matter segments. This method was confirmed in a one-dimensional simulation and was preferable to threshold and explicit (simple) masking which excluded true abnormalities.

Comparative Reliability of Total Intracranial Volume Estimation Methods and the Influence of Atrophy in a Longitudinal Semantic Dementia Cohort

Total intracranial volume (TIV) as a measure of premorbid brain size is often used to correct volumes of interest for interindividual differences in magnetic resonance imaging (MRI) studies. We directly compared the reliability of different TIV estimation methods to address whether such methods are influenced by brain atrophy in the neurodegenerative disease, semantic dementia.

Registration accuracy for VBM studies varies according to region and degenerative disease grouping

Voxel-based morphometry studies are frequently cited as having the advantage of being objective compared to region-of-interest methods. This statement assumes, however, that all regions are treated equally both in controls and diseased cohorts. This study aimed to test whether this statement is correct by analyzing fiducial landmarks in controls, Alzheimers disease (as a model of mild generalized atrophy model); Frontotemporal Dementia (focal atrophy model) and Semantic Dementia (extreme focal atrophy model). Standard SPM5 and DARTEL were evaluated using either raw or skull-stripped/bias corrected scans. The results indicated that with all methods there was variability in the degree of misregistration across regions and that there was a disease grouping interaction-most severely in the extreme focal atrophy model (Semantic Dementia). Preprocessing improved VBM outputs both with standard SPM and DARTEL. In the latter case, this occurred to an extreme degree-DARTEL using raw data was grossly insensitive to a ground truth (manually verified hippocampal atrophy in AD) whereas DARTEL after preprocessing yielded excellent results with respect to this yardstick.

A Brief History of Voxel-Based Grey Matter Analysis in Alzheimer's Disease

Voxel-based morphometry (VBM) and cortical thickness measurement are common techniques to identify regional atrophy in neurodegenerative diseases such as Alzheimers disease (AD). Because studies employing these methods draw conclusions regarding patterns of regional cortical degeneration, it is important to be aware of their possible limitations. To evaluate the effect of different VBM versions, we performed voxel-based analyses through successive versions-from SPM99 to SPM8-as well as FSL-VBM on n = 20 AD patients and n = 20 controls. Reproducibility was assessed in an independent sample, again of n = 20 per group, from the Alzheimers Disease Neuroimaging Initiative (ADNI) database. Further, we tested the hypothesis that VBM can sensitively detect hippocampal atrophy, but is relatively insensitive to changes in the cortical ribbon, by contrasting VBM with FreeSurfer cortical thickness measurements. The results with both datasets confirmed that VBM preferentially identifies grey matter lesions in the mesial temporal lobe but is largely insensitive to isocortical atrophy. In contrast, FreeSurfer identified thinning of cortical ribbon association cortex more significant in post- rather than pre-Rolandic areas and with relative preservation of primary sensory-motor regions-in other words precisely as would be expected in AD. The results highlight a bias that VBM has toward detecting mesial temporal lobe atrophy. This finding has important implications for interpretation of clinical and cognitive studies in AD.

The methyl binding domain 3/nucleosome remodelling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex

BackgroundChromatin-modifying complexes have key roles in regulating various aspects of neural stem cell biology, including self-renewal and neurogenesis. The methyl binding domain 3/nucleosome remodelling and deacetylation (MBD3/NuRD) co-repressor complex facilitates lineage commitment of pluripotent cells in early mouse embryos and is important for stem cell homeostasis in blood and skin, but its function in neurogenesis had not been described. Here, we show for the first time that MBD3/NuRD function is essential for normal neurogenesis in mice.ResultsDeletion of MBD3, a structural component of the NuRD complex, in the developing mouse central nervous system resulted in reduced cortical thickness, defects in the proper specification of cortical projection neuron subtypes and neonatal lethality. These phenotypes are due to alterations in PAX6+ apical progenitor cell outputs, as well as aberrant terminal neuronal differentiation programmes of cortical plate neurons. Normal numbers of PAX6+ apical neural progenitor cells were generated in the MBD3/NuRD-mutant cortex; however, the PAX6+ apical progenitor cells generate EOMES+ basal progenitor cells in reduced numbers. Cortical progenitor cells lacking MBD3/NuRD activity generate neurons that express both deep- and upper-layer markers. Using laser capture microdissection, gene expression profiling and chromatin immunoprecipitation, we provide evidence that MBD3/NuRD functions to control gene expression patterns during neural development.ConclusionsOur data suggest that although MBD3/NuRD is not required for neural stem cell lineage commitment, it is required to repress inappropriate transcription in both progenitor cells and neurons to facilitate appropriate cell lineage choice and differentiation programmes.

Impact of inconsistent resolution on VBM studies

This paper considers the effects of using magnetic resonance scans with different voxel dimensions in voxel-based morphometry studies. This is of potential relevance to many longitudinal studies or any ad-hoc study that relies on pre-existing databases of subjects. In order to study this effect, a group of controls were contrasted with a group of semantic dementia as well as with a group of Alzheimers disease patients using a mixture of different voxel dimensions scans on each side of the statistical test. Scans were interpolated using a sinc function in order to obtain a different voxel depth. The effects were measured by comparing the output of each analysis to the benchmark in which all scans had the original depth (and highest resolution), both visually and through the computation of the root-mean-square error difference between the resulting t-maps. It was shown that the impact is highly dependent on the scan itself, with some images showing more robustness to the interpolation process, and hence yielding fewer differences. A measure of robustness is proposed, which may be used in order to understand the impact of mixing different dimensions or adjusting them for each scan. Indiscriminate use of voxel dimensions on both groups was found to produce more errors (false positives/false negatives) than does an approach involving the use of balanced groups and a voxel dimension nuisance covariate.

MRI detection of tissue pathology beyond atrophy in Alzheimer's disease: Introducing T2-VBM

Voxel-based morphometry (VBM) of T1-weighted magnetic resonance (MR) images has been widely used to identify regional atrophy in neurodegenerative conditions such as Alzheimers disease (AD). In theory, however, T2-weighting should be more sensitive to tissue pathology, though until recently, volumetric T2-weighted images were unavailable. We tested the hypothesis that T2-VBM would be more sensitive to grey matter pathology in AD than T1-VBM using the recently-developed SPACE acquisition, which provides true-3D, high-resolution T2-weighted images. This was contrasted to conventional T1-weighted MPRAGE images acquired at the same session and resolution. All of the atrophic regions identified with T1-VBM were also identified with T2-VBM. Additional abnormalities were, however, identified with T2-VBM and the distribution of these bore a striking resemblance to the distribution of amyloid plaque deposition in AD, suggesting that T2-VBM detects signal changes due to histopathology over and above those attributable to atrophy. In keeping with this hypothesis, the relevant statistical tests demonstrated that the difference in sensitivity was caused by an apparent change in T2-weighted signal intensity that was not present in T1-weighted images. These results suggest that T2-VBM has the potential to advance VBM beyond atrophy detection to more expansive applications in tissue pathology mapping.

Disconnection as a mechanism for social cognition impairment in multiple sclerosis

Objective: To assess the contribution of microstructural normal-appearing white matter (NAWM) damage to social cognition impairment, specifically in the theory of mind (ToM), in multiple sclerosis (MS). Methods: We enrolled consecutively 60 patients with MS and 60 healthy controls (HC) matched on age, sex, and education level. All participants underwent ToM testing (Eyes Test, Videos Test) and 3T brain MRI including conventional and diffusion tensor imaging sequences. Tract-based spatial statistics (TBSS) were applied for whole-brain voxel-wise analysis of fractional anisotropy (FA) and mean diffusivity (MD) on NAWM. Results: Patients with MS performed worse on both tasks of ToM compared to HC (Eyes Test 58.7 ± 13.8 vs 81.9 ± 10.4, p < 0.001, Hedges g −1.886; Videos Test 75.3 ± 9.3 vs 88.1 ± 7.1, p < 0.001, Hedges g −1.537). Performance on ToM tests was correlated with higher values of FA and lower values of MD across widespread white matter tracts. The largest effects (≥90% of voxels with statistical significance) for the Eyes Test were body and genu of corpus callosum, fornix, tapetum, uncinate fasciculus, and left inferior cerebellar peduncle, and for the Videos Test genu and splenium of corpus callosum, fornix, uncinate fasciculus, left tapetum, and right superior fronto-occipital fasciculus. Conclusions: These results indicate that a diffuse pattern of NAWM damage in MS contributes to social cognition impairment in the ToM domain, probably due to a mechanism of disconnection within the social brain network. Gray matter pathology is also expected to have an important role; thus further research is required to clarify the neural basis of social cognition impairment in MS.

VBM with viscous fluid registration of gray matter segments in SPM

Improved registration of gray matter segments in SPM has been achieved with the DARTEL algorithm. Previous work from our group suggested, however, that such improvements may not translate to studies of clinical groups. To address the registration issue in atrophic brains, this paper relaxed the condition of diffeomorphism, central to DARTEL, and made use of a viscous fluid registration model with limited regularization constraints to register the modulated gray matter probability maps to an intra-population template. Quantitative analysis of the registration results after the additional viscous fluid step showed no worsening of co-localization of fiducials compared to DARTEL or unified segmentation methods, and the resulting voxel based morphometry (VBM) analyses were able to better identify atrophic regions and to produce results with fewer apparent false positives. DARTEL showed great sensitivity to atrophy, but the resulting VBM maps presented broad, amorphous regions of significance that are hard to interpret. We propose that the condition of diffeomorphism is not necessary for basic VBM studies in atrophic populations, but also that it has disadvantages that must be taken into consideration before a study. The presented viscous fluid registration method is proposed for VBM studies to enhance sensitivity and localizing power.