Complex spatial and temporally defined myelin and axonal degeneration in Huntington disease.

Although much prior work has focused on the basal ganglia and cortical pathology that defines Huntington's disease (HD), recent studies have also begun to characterize cerebral white matter damage (Rosas et al., 2006; Dumas et al., 2012; Poudel et al., 2014). In this study, we investigated differences in the large fascicular bundles of the cerebral white matter of gene-positive HD carriers, including pre-manifest individuals and early symptomatic patients, using recently developed diffusion tractography procedures. We examined eighteen major fiber bundles in 37 patients with early HD (average age 55.2 ±â€¯11.5, 14 male, 23 female), 31 gene-positive, motor negative pre-symptomatic HD (PHD) (average age 48.1 ±â€¯11.5, 13 male, 18 female), and 38 healthy age-matched controls (average age 55.7 ±â€¯8.6, 14 male, 24 female), using the TRActs Constrained by UnderLying Anatomy (TRACULA) procedure available as part of the FreeSurfer image processing software package. We calculated the mean fractional anisotropy (FA) and the mean radial (RD) and axial diffusivities (AD) for each fiber bundle. We also evaluated the relationships between diffusion measures, cognition and regional cortical thinning. We found that early changes in RD of select tracts in PHD subjects were associated with impaired performance on neuropsychological tests, suggesting that early changes in myelin might underlie early cognitive dysfunction. Finally, we found that increases in AD of select tracts were associated with regionally select cortical thinning of areas known to atrophy in HD, including the sensorimotor, supramarginal and fusiform gyrus, suggesting that AD may be reflecting pyramidal cell degeneration in HD. Together, these results suggest that white matter microstructural changes in HD reflect a complex, clinically relevant and dynamic process.

SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans.

Methylation of the SKA2 (spindle and kinetochore-associated complex subunit 2) gene has recently been identified as a promising biomarker of suicide risk. Based on this finding, we examined associations between SKA2 methylation, cortical thickness and psychiatric phenotypes linked to suicide in trauma-exposed veterans. About 200 trauma-exposed white non-Hispanic veterans of the recent conflicts in Iraq and Afghanistan (91% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. Of all, 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the cytosine-guanine locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated single nucleotide polymorphism (rs7208505) in relationship to whole-brain cortical thickness, posttraumatic stress disorder symptoms (PTSD) and depression symptoms. Whole-brain vertex-wise analyses identified three clusters in prefrontal cortex that were associated with genotype-adjusted SKA2 DNA methylation (methylation(adj)). Specifically, DNA methylation(adj) was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylation(adj) and negatively correlated with cortical thickness in these regions. Mediation analyses showed a significant indirect effect of PTSD on cortical thickness via SKA2 methylation status. Results suggest that DNA methylation(adj) of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.

Therapeutic enquiries about biological agents as a tool to identify safety aspects and patterns of use.

BACKGROUND: Biotechnological agents (BA) are increasingly being used in clinical practice. We aimed to determine, whether enquiries about them to a therapeutic consultation service have also become more frequent, and to describe the information requested in these consultations. METHODS: We retrospectively reviewed 14 104 therapeutic consultations collected in a computerised database between 2000 and 2014. Enquiries about BA (monoclonal antibodies, fusion proteins or cytokine antagonists) were chosen. Information on the type of BA, underlying condition, type of enquiry and affiliation of the enquirer was retrieved and compared with data from consultations about other agents. RESULTS: During the study period, 365 enquiries about 30 different BA were received. Only 4% of them were received before 2004, while 48.8% were received after 2010. Rituximab, infliximab, adalimumab and etanercept were most frequently enquired about. Agent selection (n=184) and/or adverse effects (n=174) were the most frequent reasons for making an enquiry. Most enquiries about an agent selection were made about an off-label use (n=164), mainly for systemic autoimmune diseases (n=61). Over half of the enquiries about adverse effects were about their teratogenic potential (n=96). Enquiries about BA more often requested an opinion (87.7% vs 77.7%) were made by physicians (89.9% vs 76.9%), from a hospital (81.6% vs 44.5%) and regarded a specific patient (87.4% vs 74.5%). CONCLUSIONS: Therapeutic consultations about BA are increasing. Most of them are related to uncertainties of health professionals regarding any new medicine: their off-label use, actual adverse effects or the teratogenic potential of the involved agents.

Tract-based analysis of white matter degeneration in Alzheimer's disease.

Although much prior work has focused on the known cortical pathology that defines Alzheimer's disease (AD) histologically, recent work has additionally demonstrated substantial damage to the cerebral white matter in this condition. While there is large evidence of diffuse damage to the white matter in AD, it is unclear whether specific white matter tracts exhibit a more accelerated pattern of damage and whether the damage is associated with the classical neurodegenerative changes of AD. In this study, we investigated microstructural differences in the large fascicular bundles of the cerebral white matter of individuals with AD and mild cognitive impairment (MCI), using recently developed automated diffusion tractography procedures in the Alzheimer's disease Neuroimaging Initiative (ADNI) dataset. Eighteen major fiber bundles in a total of 36 individuals with AD, 81 MCI and 60 control participants were examined with the TRActs Constrained by UnderLying Anatomy (TRACULA) procedure available as part of the FreeSurfer image processing software package. For each fiber bundle, the mean fractional anisotropy (FA), and mean, radial and axial diffusivities were calculated. Individuals with AD had increased diffusivities in both left and right cingulum-angular bundles compared to control participants (p<0.001). Individuals with MCI also had increased axial and mean diffusivities and increased FA in both cingulum-angular bundles compared to control participants (p<0.05) and decreased radial diffusivity compared to individuals with AD (p<0.05). We additionally examined how white matter deterioration relates to hippocampal volume, a traditional imaging measure of AD pathology, and found the strongest negative correlations in AD patients between hippocampal volume and the diffusivities of the cingulum-angular and cingulum-cingulate gyrus bundles and of the corticospinal tracts (p<0.05). However, statistically controlling for hippocampal volume did not remove all group differences in white matter measures, suggesting a unique contribution of white matter damage to AD unexplained by this disease biomarker. These results suggest that (1) AD-associated deterioration of white matter fibers is greatest in tracts known to be connected to areas of pathology in AD and (2) lower white matter tract integrity is more diffusely associated with lower hippocampal volume indicating that the pathology in the white matter follows to some degree the neurodegenerative staging and progression of this condition.

Imaging small vessel-associated white matter changes in aging.

Alterations in cerebrovascular structure and function may underlie the most common age-associated cognitive, psychiatric, and neurological conditions presented by older adults. Although much remains to understand, existing research suggests several age-associated detrimental conditions may be mediated through sometimes subtle small vessel-induced damage to the cerebral white matter. Here we review a selected portion of the vast work that demonstrates links between changes in vascular and neural health as a function of advancing age, and how even changes in low-to-moderate risk individuals, potentially beginning early in the adult age-span, may have an important impact on functional status in late life.

Correlations between MRI white matter lesion location and executive function and episodic memory.

OBJECTIVES: MRI white matter hyperintensity (WMH) volume is associated with cognitive impairment. We hypothesized that specific loci of WMH would correlate with cognition even after accounting for total WMH volume. METHODS: Subjects were identified from a prospective community-based study: 40 had normal cognition, 94 had mild impairment (defined here as a Clinical Dementia Rating [CDR] score of 0.5 without dementia), and 11 had mild Alzheimer's dementia. Factor analysis of a 22-item neuropsychological battery yielded 4 factors (episodic memory, executive function, spatial skills, and general knowledge). MRI WMH segmentation and analysis was performed using FreeSurfer software. RESULTS: Higher WMH volume was independently associated with lower executive function and episodic memory factor scores. Voxel-based general linear models showed loci where WMH was strongly inversely associated with specific cognitive factor scores (p < 0.001), controlling for age, education, sex, APOE genotype, and total WMH volume. For episodic memory, clusters were observed in bilateral temporal-occipital and right parietal periventricular white matter, and the left anterior limb of the internal capsule. For executive function, clusters were observed in bilateral inferior frontal white matter, bilateral temporal-occipital and right parietal periventricular white matter, and the anterior limb of the internal capsule bilaterally. CONCLUSIONS: Specific WMH loci are closely associated with executive function and episodic memory, independent of total WMH volume. The anatomic locations suggest that WMH may cause cognitive impairment by affecting connections between cortex and subcortical structures, including the thalamus and striatum, or connections between the occipital lobe and frontal or parietal lobes.

Hippocampal degeneration is associated with temporal and limbic gray matter/white matter tissue contrast in Alzheimer's disease.

Recent studies have demonstrated alterations in cortical gray to white matter tissue contrast with nondemented aging and in individuals with Alzheimer's disease (AD). However, little information exists about the clinical relevance of such changes. It is possible that changes in MRI tissue contrast occur via independent mechanisms from those traditionally used in the assessment of AD associated degeneration such as hippocampal degeneration measured by more traditional volumetric magnetic resonance imaging (MRI). We created cortical surface models of 95 cognitively healthy individuals and 98 individuals with AD to characterize changes in regional gray and white matter T1-weighted signal intensities in dementia and to evaluate how such measures related to classically described hippocampal and cortical atrophy. We found a reduction in gray matter to white matter tissue contrast throughout portions of medial and lateral temporal cortical regions as well as in anatomically associated regions including the posterior cingulate, precuneus, and medial frontal cortex. Decreases in tissue contrast were associated with hippocampal volume, however, the regional patterns of these associations differed for demented and nondemented individuals. In nondemented controls, lower hippocampal volume was associated with decreased gray/white matter tissue contrast globally across the cortical mantle. In contrast, in individuals with AD, selective associations were found between hippocampal volume and tissue contrast in temporal and limbic tissue. These results demonstrate that there are strong regional changes in neural tissue properties in AD which follow a spatial pattern including regions known to be affected from pathology studies. Such changes are associated with traditional imaging metrics of degeneration and may provide a unique biomarker of the tissue loss that occurs as a result of AD.

Tapping linked to function and structure in premanifest and symptomatic Huntington disease.

OBJECTIVE: Motor signs are functionally disabling features of Huntington disease. Characteristic motor signs define disease manifestation. Their severity and onset are assessed by the Total Motor Score of the Unified Huntington's Disease Rating Scale, a categorical scale limited by interrater variability and insensitivity in premanifest subjects. More objective, reliable, and precise measures are needed which permit clinical trials in premanifest populations. We hypothesized that motor deficits can be objectively quantified by force-transducer-based tapping and correlate with disease burden and brain atrophy. METHODS: A total of 123 controls, 120 premanifest, and 123 early symptomatic gene carriers performed a speeded and a metronome tapping task in the multicenter study TRACK-HD. Total Motor Score, CAG repeat length, and MRIs were obtained. The premanifest group was subdivided into A and B, based on the proximity to estimated disease onset, the manifest group into stages 1 and 2, according to their Total Functional Capacity scores. Analyses were performed centrally and blinded. RESULTS: Tapping variability distinguished between all groups and subgroups in both tasks and correlated with 1) disease burden, 2) clinical motor phenotype, 3) gray and white matter atrophy, and 4) cortical thinning. Speeded tapping was more sensitive to the detection of early changes. CONCLUSION: Tapping deficits are evident throughout manifest and premanifest stages. Deficits are more pronounced in later stages and correlate with clinical scores as well as regional brain atrophy, which implies a link between structure and function. The ability to track motor phenotype progression with force-transducer-based tapping measures will be tested prospectively in the TRACK-HD study.

White matter pathology isolates the hippocampal formation in Alzheimer's disease.

Prior work has demonstrated that the memory dysfunction of Alzheimer's disease (AD) is accompanied by marked cortical pathology in medial temporal lobe (MTL) gray matter. In contrast, changes in white matter (WM) of pathways associated with the MTL have rarely been studied. We used diffusion tensor imaging (DTI) to examine regional patterns of WM tissue changes in individuals with AD. Alterations of diffusion properties with AD were found in several regions including parahippocampal WM, and in regions with direct and secondary connections to the MTL. A portion of the changes measured, including effects in the parahippocampal WM, were independent of gray matter degeneration as measured by hippocampal volume. Examination of regional changes in unique diffusion parameters including anisotropy and axial and radial diffusivity demonstrated distinct zones of alterations, potentially stemming from differences in underlying pathology, with a potential myelin specific pathology in the parahippocampal WM. These results demonstrate that deterioration of neocortical connections to the hippocampal formation results in part from the degeneration of critical MTL and associated fiber pathways.

Age-associated alterations in cortical gray and white matter signal intensity and gray to white matter contrast.

Prior studies have focused on patterns of brain atrophy with aging and age-associated cognitive decline. It is possible that changes in neural tissue properties could provide an important marker of more subtle changes compared to gross morphometry. However, little is known about how MRI tissue parameters are altered in aging. We created cortical surface models of 148 individuals and mapped regional gray and white matter T1-weighted signal intensities from 3D MPRAGE images to examine patterns of age-associated signal alterations. Gray matter intensity was decreased with aging with strongest effects in medial frontal, anterior cingulate, and inferior temporal regions. White matter signal intensity decreased with aging in superior and medial frontal, cingulum, and medial and lateral temporal regions. The gray/white ratio (GWR) was altered throughout a large portion of the cortical mantle, with strong changes in superior and inferior frontal, lateral parietal, and superior temporal and precuneus regions demonstrating decreased overall contrast. Statistical effects of contrast changes were stronger than those of cortical thinning. These results demonstrate that there are strong regional changes in neural tissue properties with aging and tissue intensity measures may serve as an important biomarker of degeneration.

QA/acceptance testing of DEXA X-ray systems used in bone mineral densitometry.

New developments in dual energy X-ray absorptiometry (DEXA) imaging technology [fan beam and cone beam (CB)] result in higher exposure levels, shorter scan times, increased patient throughput and increased shielding requirements. This study presents the results of a European survey detailing the number and location of DEXA systems in SENTINEL partner states and the QA (quality assurance) currently performed by physicists and operators in these centres. The results of a DEXA equipment survey based on an in-house developed QA protocol are presented. Measurements show that the total effective dose to the patient from a spine and dual femur DEXA examination on the latest generation DEXA systems is comparable with a few microSv at most. Scatter measurements showed that the use of a mobile lead screen for staff protection was necessary for fan and CB systems. Scattered dose from newer generation systems may also exceed the exposure limits for the general public so structural shielding may also be required. Considerable variation in the magnitude and annual repeatability of half value layer was noted between different models of DEXA scanners. A comparative study of BMD (bone mineral density) accuracy using the European Spine Phantom highlighted a deviation of up to 7% in BMD values between scanners of different manufacturers.

Quality control measurements for fluoroscopy systems in eight countries participating in the SENTINEL EU coordination action.

Quality control (QC) is becoming increasingly important in relation to the introduction of digital medical imaging systems using X rays. It was, therefore, decided to organise and perform a trial on image quality and physical measurements. The SENTINEL toolkit for QC measurements of fluoroscopy systems containing equipment and instructions for their use in the assessment of dose and image quality circulated among participants in the trial. The participants reported on their results. In the present contribution, the impact of the trial on the selected protocols is presented. The Medical Physics and Bioengineering protocol appeared to be useful for QC, and also for digital systems. The protocol needs an additional section, or an addition to each section, to state compliance with the requirements. The circular cross-sections of the Leeds test objects need adaptation for rectangular flat panel detector (FPD) systems. Only one participant was able to perform the monitor test using MoniQA. This is due to the fact that assistance is required from the suppliers of the X-ray systems. This problem needs to be solved to apply MoniQA in practice.

Reference levels at European level for cardiac interventional procedures.

In interventional cardiology, a wide variation in patient dose for the same type of procedure has been recognised by different studies. Variation is almost due to procedure complexity, equipment performance, procedure protocol and operator skill. The SENTINEL consortium has performed a survey in nine european centres collecting information on near 2000 procedures, and a new set of reference levels (RLs) for coronary angiography and angioplasty and diagnostic electrophysiology has been assessed for air kerma-area product: 45, 85 and 35 Gy cm2, effective dose: 8, 15 and 6 mSv, cumulative dose at interventional reference point: 650 and 1500 mGy, fluoroscopy time: 6.5, 15.5 and 21 min and cine frames: 700 and 1000 images, respectively. Because equipment performance and set-up are the factors contributing to patient dose variability, entrance surface air kerma for fluoroscopy, 13 mGy min(-1), and image acquisition, 0.10 mGy per frame, have also been proposed in the set of RLs.

Survey on performance assessment of cardiac angiography systems.

Advances in imaging technology have facilitated the development of increasingly complex interventional cardiac equipment. Consequently, there is a need for definitive equipment requirements. The aim of the study is to assess the performances of different cardiac angiographic systems. A questionnaire was sent to centres participating in SENTINEL Project to collect dosimetry data (typical entrance dose rate in fluoroscopy and imaging mode), image quality evaluations (low and high contrast resolutions) and KAP calibration factors. Results from this survey could contribute to the explanation of patient dose variability in angiographic cardiac procedures and to derive reference levels for cardiac angiographic equipment performance parameters.

Patient doses and image quality in digital chest radiology.

Chest X-ray examination is one of the most frequently required procedures used in clinical practice. For studying the image quality of different X-ray digital systems and for the control of patient doses during chest radiological examinations, the standard anthropomorphic lung/chest phantom RSD 330 has been used and exposed in different digital modalities available in Slovakia. To compare different techniques of chest examination, a special software has been developed that enables researchers to compare digital imaging and communications in medicine header images from different digital modalities, using a special viewer. In this paper, this special software has been used for an anonymous correspondent audit for testing image quality evaluation by comparing various parameters of chest imaging, evaluated by 84 Slovak radiologists. The results of the comparison have shown that the majority of the participating radiologists felt that the highest image quality is reached with a flat panel, assessed by the entrance surface dose value, which is approximately 75% lower than the diagnostic reference level of chest examination given in the Slovak legislation. Besides the results of the audit, the possibilities of using the software for optimisation, education and training of medical students, radiological assistants, physicists and radiologists in the field of digital radiology will be described.

Patient dose in interventional radiology: a European survey.

Patient doses for a few common fluoroscopy-guided procedures in interventional radiology (IR) (excluding cardiology) were collected from a few radiological departments in 13 European countries. The major aim was to evaluate patient doses for the basis of the reference levels. In total, data for 20 procedures for about 1300 patients were collected. There were many-fold variations in the number of IR equipment and procedures per population, in the entrance dose rates, and in the patient dose data (total dose area product or DAP, fluoroscopy time and number of frames). There was no clear correlation between the total DAP and entrance dose rate, or between the total DAP and fluoroscopy time, indicating that a number of parameters affect the differences. Because of the limited number of patients, preliminary reference levels were proposed only for a few procedures. There is a need to improve the optimisation of IR procedures and their definitions and grouping, in order to account for their different complexities.

Detection of cortical thickness correlates of cognitive performance: Reliability across MRI scan sessions, scanners, and field strengths.

In normal humans, relationships between cognitive test performance and cortical structure have received little study, in part, because of the paucity of tools for measuring cortical structure. Computational morphometric methods have recently been developed that enable the measurement of cortical thickness from MRI data, but little data exist on their reliability. We undertook this study to evaluate the reliability of an automated cortical thickness measurement method to detect correlates of interest between thickness and cognitive task performance. Fifteen healthy older participants were scanned four times at 2-week intervals on three different scanner platforms. The four MRI data sets were initially treated independently to investigate the reliability of the spatial localization of findings from exploratory whole-cortex analyses of cortical thickness-cognitive performance correlates. Next, the first data set was used to define cortical ROIs based on the exploratory results that were then applied to the remaining three data sets to determine whether the relationships between cognitive performance and regional cortical thickness were comparable across different scanner platforms and field strengths. Verbal memory performance was associated with medial temporal cortical thickness, while visuomotor speed/set shifting was associated with lateral parietal cortical thickness. These effects were highly reliable - in terms of both spatial localization and magnitude of absolute cortical thickness measurements - across the four scan sessions. Brain-behavior relationships between regional cortical thickness and cognitive task performance can be reliably identified using an automated data analysis system, suggesting that these measures may be useful as imaging biomarkers of disease or performance ability in multicenter studies in which MRI data are pooled.

Neuroimaging H.M.: a 10-year follow-up examination.

In 1997, Corkin et al. described the anatomical boundaries of the amnesic patient H.M.'s surgical resection, based on a comprehensive analysis of magnetic resonance imaging (MRI) scans collected in 1992 and 1993 (Corkin et al. (1997) J Neurosci 17:3964-3979). We subsequently scanned H.M. on several occasions, employing more advanced data acquisition and analysis methods, and now describe additional details about his brain anatomy and pathology. This account combines results from high-resolution T1-weighted scans, which provide measures of cortical and subcortical morphometry, diffusion tensor images, which provide quantitative information about white matter microstructure and the anatomy of major fasciculi, and T2-weighted images, which highlight damage to deep white matter. We applied new MRI analysis techniques to these scans to assess the integrity of areas throughout H.M.'s brain. We documented a number of new changes, including cortical thinning, atrophy of deep gray matter structures, and a large volume of abnormal white matter and deep gray matter signal. Most of these alterations were not apparent in his prior scans, suggesting that they are of recent origin. Advanced age and hypertension likely contributed to these new findings.

Regional cortical thinning in preclinical Huntington disease and its relationship to cognition.

The authors studied presymptomatic individuals with the Huntington disease (HD) mutation to determine whether cortical thinning was present. They found thinning that was regionally selective, semi-independent of striatal volume loss, and correlated with cognitive performance. Early, extensive cortical involvement occurs during the preclinical stages of HD.