Emerging magnetic resonance imaging techniques and analysis methods in amyotrophic lateral sclerosis

Objective markers of disease sensitive to the clinical activity, symptomatic progression, and underlying substrates of neurodegeneration are highly coveted in amyotrophic lateral sclerosis in order to more eloquently stratify the highly heterogeneous phenotype and facilitate the discovery of effective disease modifying treatments for patients. Magnetic resonance imaging (MRI) is a promising, non-invasive biomarker candidate whose acquisition techniques and analysis methods are undergoing constant evolution in the pursuit of parameters which more closely represent biologically-applicable tissue changes. Neurite Orientation Dispersion and Density Imaging (NODDI; a form of diffusion imaging), and quantitative Magnetization Transfer Imaging (qMTi) are two such emerging modalities which have each broadened the understanding of other neurological disorders and have the potential to provide new insights into structural alterations initiated by the disease process in ALS. Furthermore, novel neuroimaging data analysis approaches such as Event-Based Modeling (EBM) may be able to circumvent the requirement for longitudinal scanning as a means to comprehend the dynamic stages of neurodegeneration . Combining these and other innovative imaging protocols with more sophisticated techniques to analyse ever-increasing datasets holds the exciting prospect of transforming understanding of the biological processes and temporal evolution of the ALS syndrome, and can only benefit from multicentre collaboration across the entire ALS research community

Neurite orientation and dispersion density imaging (NODDI) detects cortical and corticospinal tract degeneration in ALS

Background: Corticospinal tract (CST) degeneration and cortical atrophy are consistent features of amyotrophic lateral sclerosis (ALS). We hypothesised that neurite orientation dispersion and density imaging (NODDI), a multicompartment model of diffusion MRI, would reveal microstructural changes associated with ALS within the CST and precentral gyrus (PCG) ‘in vivo’. Methods: 23 participants with sporadic ALS and 23 healthy controls underwent diffusion MRI. Neurite density index (NDI), orientation dispersion index (ODI) and free water fraction (isotropic compartment (ISO)) were derived. Whole brain voxel-wise analysis was performed to assess for group differences. Standard diffusion tensor imaging (DTI) parameters were computed for comparison. Subgroup analysis was performed to investigate for NODDI parameter differences relating to bulbar involvement. Correlation of NODDI parameters with clinical variables were also explored. The results were accepted as significant where p<0.05 after family-wise error correction at the cluster level, clusters formed with p<0.001. Results: In the ALS group NDI was reduced in the extensive regions of the CST, the corpus callosum and the right PCG. ODI was reduced in the right anterior internal capsule and the right PCG. Significant differences in NDI were detected between subgroups stratified according to the presence or absence of bulbar involvement. ODI and ISO correlated with disease duration. Conclusions: NODDI demonstrates that axonal loss within the CST is a core feature of degeneration in ALS. This is the main factor contributing to the altered diffusivity profile detected using DTI. NODDI also identified dendritic alterations within the PCG, suggesting microstructural cortical dendritic changes occur together with CST axonal damage

Emerging Magnetic Resonance Imaging Techniques and Analysis Methods in Amyotrophic Lateral Sclerosis

Objective markers of disease sensitive to the clinical activity, symptomatic progression, and underlying substrates of neurodegeneration are highly coveted in amyotrophic lateral sclerosis in order to more eloquently stratify the highly heterogeneous phenotype and facilitate the discovery of effective disease modifying treatments for patients. Magnetic resonance imaging (MRI) is a promising, non-invasive biomarker candidate whose acquisition techniques and analysis methods are undergoing constant evolution in the pursuit of parameters which more closely represent biologically-applicable tissue changes. Neurite Orientation Dispersion and Density Imaging (NODDI; a form of diffusion imaging), and quantitative Magnetization Transfer Imaging (qMTi) are two such emerging modalities which have each broadened the understanding of other neurological disorders and have the potential to provide new insights into structural alterations initiated by the disease process in ALS. Furthermore, novel neuroimaging data analysis approaches such as Event-Based Modeling (EBM) may be able to circumvent the requirement for longitudinal scanning as a means to comprehend the dynamic stages of neurodegeneration in vivo. Combining these and other innovative imaging protocols with more sophisticated techniques to analyse ever-increasing datasets holds the exciting prospect of transforming understanding of the biological processes and temporal evolution of the ALS syndrome, and can only benefit from multicentre collaboration across the entire ALS research community

Evolution of white matter damage in amyotrophic lateral sclerosis

Objective To characterize disease evolution in amyotrophic lateral sclerosis using an event‐based model designed to extract temporal information from cross‐sectional data. Conventional methods for understanding mechanisms of rapidly progressive neurodegenerative disorders are limited by the subjectivity inherent in the selection of a limited range of measurements, and the need to acquire longitudinal data. Methods The event‐based model characterizes a disease as a series of events, each comprising a significant change in subject state. The model was applied to data from 154 patients and 128 healthy controls selected from five independent diffusion MRI datasets acquired in four different imaging laboratories between 1999 and 2016. The biomarkers modeled were mean fractional anisotropy values of white matter tracts implicated in amyotrophic lateral sclerosis. The cerebral portion of the corticospinal tract was divided into three segments. Results Application of the model to the pooled datasets revealed that the corticospinal tracts were involved before other white matter tracts. Distal corticospinal tract segments were involved earlier than more proximal (i.e., cephalad) segments. In addition, the model revealed early ordering of fractional anisotropy change in the corpus callosum and subsequently in long association fibers. Interpretation These findings represent data‐driven evidence for early involvement of the corticospinal tracts and body of the corpus callosum in keeping with conventional approaches to image analysis, while providing new evidence to inform directional degeneration of the corticospinal tracts. This data‐driven model provides new insight into the dynamics of neuronal damage in amyotrophic lateral sclerosis

The Ionized Gas and Nuclear Environment in NGC 3783. I. Time-Averaged 900 ks Chandra Grating Spectroscopy

We present results from a 900 ks exposure of NGC 3783 with the High-Energy Transmission Grating Spectrometer on board the Chandra X-ray Observatory. The resulting X-ray spectrum has the best combination of signal-to-noise and resolution ever obtained for an AGN. This spectrum reveals absorption lines from H-like and He-like ions of N, O, Ne, Mg, Al, Si, and S. There are also possible absorption lines from H-like and He-like Ar and Ca. We also identify inner-shell absorption from lower-ionization ions such as Si_VII-Si_XII and S_XII-S_XIV. The iron absorption spectrum is very rich; L-shell lines of Fe_XVII-Fe_XXIV are detected, strong complex of M-shell lines, and probable resonance lines from Fe_XXV. The absorption lines are blueshifted relative to the systemic velocity by a mean velocity of -590+-150 km/s. We resolve many of the absorption lines, and their mean FWHM is 820+-280 km/s. We do not find correlations between the velocity shifts or the FWHMs with the ionization potentials of the ions. Most absorption lines show asymmetry, having more extended blue wings than red wings. In O_VII we have resolved this asymmetry to be from an additional absorption system at ~ -1300 km/s. The two X-ray absorption systems are consistent in velocity shift and FWHM with the ones identified in the UV lines of C IV, N V, and H I. Equivalent width measurements for all lines are given and column densities are calculated for several ions. We resolve the narrow Fe_K\alpha line at 6398.2+-3.3 eV to have a FWHM of 1720+-360 km/s, which suggests that this narrow line may be emitted from the outer part of the broad line region or the inner part of the torus. We also detect a `Compton shoulder' redward of the narrow Fe_K\alpha line which indicates that it arises in cold, Compton-thick gas.Comment: 19 pages, 12 figures (2 in color), emulateapj5, accepted for publication in The Astrophysical Journal Supplement

High resolution X-ray spectroscopy of the Seyfert 1 Mrk841: insights into the warm absorber and warm emitter

The Seyfert 1 galaxy Mrk841 was observed five times between 2001 and 2005 by the XMM-Newton X-ray observatory. The source is well known for showing spectral complexity in the variable iron line and in the soft X-ray excess. This paper reports on the first study of Mrk841 soft X-ray spectrum at high spectral resolution. The availability of multiple exposures obtained by the Reflection Grating Spectrometer (RGS) cameras allows a thorough study of the complex absorption and emission spectral features in the soft X-ray band.The three combined exposures obtained in January 2001 and the two obtained in January and July 2005 were analysed using the SPEX software. We detect a two-phase warm absorber: a medium ionisation component (logxi~1.5-2.2 ergs s cm^{-1}) is responsible for a deep absorption feature in the Unresolved Transition Array of the Fe M-shell and for several absorption lines in the OVI-VIII band; a higher ionisation phase with logxi~3 ergs s cm^{-1} is required to fit absorption in the NeIX-X band. The ionisation state and the column density of the gas present moderate variation from 2001 to 2005 for both phases. The high ionisation component of the warm absorber has no effect in the Fe K band. No significant velocity shift of the absorption lines is measured in the RGS data. Remarkably, the 2005 spectra show emission features consistent with photoionisation in a high density (n_e>10^{11} cm^{-3}) gas: a prominent OVII line triplet is clearly observed in January 2005 and narrow Radiative Recombination Continua (RRC) of OVII and CVI are observed in both 2005 data sets. A broad Gaussian line around 21.7 Angstrom is also required to fit all the data sets. The derived radial distance for the emission lines seems to suggest that the photoionisation takes place within the optical Broad Line Region of the source.Comment: In press on A&A, replaced version includes language editing and typo on velocities corrected in Table

Radio and X-ray emission from disc winds in radio-quiet quasars

It has been proposed that the radio spectra of radio-quiet quasars is produced by free-free emission in the optically thin part of an accretion disc wind. An important observational constraint on this model is the observed X-ray luminosity. We investigate this constraint using a sample of PG radio-quiet quasars for which XMM-Newton EPIC spectra are available. Comparing the predicted and measured luminosities for 0.5, 2 and 5 keV, we conclude that all of the studied PG quasars require a large hydrogen column density absorber, requiring these quasars to be close to or Compton-thick. Such a large column density can be directly excluded for PG 0050+124, for which a high-resolution RGS spectrum exists. Further constraint on the column density for a further 19 out of the 21 studied PG quasars comes from the EPIC spectrum characteristics such as hard X-ray power-law photon index and the equivalent width of the Fe Kalpha line; and the small equivalent width of the C IV absorber present in UV spectra. For 2 sources: PG 1001+054 and PG 1411+442 we cannot exclude that they are indeed Compton-thick, and the radio and X-ray luminosity are due to a wind originating close to the super-massive black hole. We conclude that for 20 out of 22 PG quasars studied free-free emission from a wind emanating from the accretion disc cannot mutually explain the observed radio and X-ray luminosity.Comment: Accepted for publication in MNRAS, 10 pages, 5 figure

XMM-Newton unveils the complex iron K alpha region of Mrk 279

We present the results of a ~160 ks-long XMM-Newton observation of the Seyfert 1 galaxy Mrk 279. The spectrum shows evidence of both broad and narrow emission features. The Fe K alpha line may be equally well explained by a single broad Gaussian (FWHM~10,000 km/s) or by two components: an unresolved core plus a very broad profile (FWHM~14,000 km/s). For the first time we quantified, via the "locally optimally emitting cloud" model, the contribution of the broad line region (BLR) to the absolute luminosity of the broad component of the Fe K alpha at 6.4 keV. We find that the contribution of the BLR is only ~3%. In the two-line component scenario, we also evaluated the contribution of the highly ionized gas component, which produces the FeXXVI line in the iron K region. This contribution to the narrow core of the Fe K alpha line is marginal <0.1%. Most of the luminosity of the unresolved, component of Fe K alpha may come from the obscuring torus, while the very-broad associated component may come from the accretion disk. However, models of reflection by cold gas are difficult to test because of the limited energy band. The FeXXVI line at 6.9 keV is consistent to be produced in a high column density (N_H~10^23 cm^{-2}), extremely ionized (log\xi~5.5-7) gas. This gas may be a highly ionized outer layer of the torus.Comment: 10 pages, 9 figures, accepted for publication in Astronomy and Astrophysic

Deficits in neurite density underlie white matter structure abnormalities in first-episode psychosis

Background: Structural abnormalities across multiple white matter tracts are recognised in people with early psychosis, consistent with dysconnectivity as a neuropathological account of symptom expression. We applied advanced neuroimaging techniques to characterise microstructural white matter abnormalities for a deeper understanding of the developmental aetiology of psychosis. Methods: Thirty-five first-episode psychosis patients, and 19 healthy controls, participated in a quantitative neuroimaging study using Neurite Orientation Dispersion and Density Imaging (NODDI), a multi-shell diffusion-weighted MRI technique that distinguishes white matter fibre arrangement and geometry from changes in neurite density. Fractional anisotropy (FA) and mean diffusivity images were also derived. Tract-based spatial statistics compared white matter structure between patients and controls and tested associations with age, symptom severity and medication. Results: Patients with first-episode psychosis had lower regional FA in multiple commissural, corticospinal, and association tracts. These abnormalities predominantly colocalized with regions of reduced neurite density, rather than aberrant fibre bundle arrangement (orientation dispersion index). There was no direct relationship with active symptomatology. FA decreased and orientation dispersion index increased with age in patients, but not controls, suggesting accelerated effects of white matter geometry change. Conclusions: Deficits in neurite density appear fundamental to abnormalities in white matter integrity in early psychosis. In the first application of NODDI in psychosis, we found that processes compromising axonal fibre number, density, and myelination, rather than processes leading to spatial disruption of fibre organisation, are implicated in the aetiology of the disorder. This accords with a neurodevelopmental origin of aberrant brain-wide structural connectivity predisposing individuals to psychosis