A variant in GRN of Spanish origin presenting with heterogeneous phenotypes.

INTRODUCTION: The variant c.1414-1G>T in the GRN gene has previously been reported as probably pathogenic in subjects of Hispanic origin in the American continent. METHODS: We report 5 families of Spanish origin carrying this variant, including the clinical, neuroimaging, and laboratory findings. RESULTS: Phenotypes were strikingly different, including cases presenting with behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, rapidly progressive motor neuron disease (pathologically documented), and tremor-dominant parkinsonism. Retinal degeneration has been found in homozygous carriers only. Ex vivo splicing assays confirmed that the mutation c.1414-1G>T affects the splicing of the exon, causing a loss of 20 amino acids in exon 11. CONCLUSIONS: We conclude that variant c.1414-1G>T of the GRN gene is pathogenic, can lead to a variety of clinical presentations and to gene dosage effect, and probably has a Spanish founder effect.

Cortical differences in diverticular disease and correlation with symptom reports.

BACKGROUND: Recent studies have shown that the brain of patients with gastrointestinal disease differ both structurally and functionally from that of controls. Highly somatizing diverticular disease (HSDD) patients were also shown to differ from low somatizing (LSDD) patients functionally. This study aimed to investigate how they differed structurally. METHODS: Four diseases subgroups were studied in a cross-sectional design: 20 patients with asymptomatic diverticular disease (ADD), 18 LSDD, 16 HSDD, and 18 with irritable bowel syndrome. We divided DD patients into LSDD and HSDD using a cutoff of 6 on the Patient Health Questionnaire 12 Somatic Symptom (PHQ12-SS) scale. All patients underwent a 1-mm isotropic structural brain MRI scan and were assessed for somatization, hospital anxiety, depression, and pain catastrophizing. Whole brain volumetry, cortical thickness analysis and voxel-based morphometry were carried out using Freesurfer and SPM. KEY RESULTS: We observed decreases in gray matter density in the left and right dorsolateral prefrontal cortex (dlPFC), and in the mid-cingulate and motor cortex, and increases in the left (19, 20) and right (19, 38) Brodmann Areas. The average cortical thickness differed overall across groups (P = .002) and regionally: HSDD > ADD in the posterior cingulate cortex (P = .03), HSDD > LSDD in the dlPFC (P = .03) and in the ventrolateral PFC (P < .001). The thickness of the anterior cingulate cortex and of the mid-prefrontal cortex were also found to correlate with Pain Catastrophizing (Spearman's ρ = 0.24, P = .043 uncorrected and Spearman's ρ = 0.25, P = .03 uncorrected). CONCLUSION & INFERENCES: This is the first study of structural gray matter abnormalities in diverticular disease patients. The data show brain differences in the pain network.

Improved detection of focal cortical lesions using 7T magnetisation transfer imaging in patients with multiple sclerosis.

BACKGROUND: Cortical lesions account for a larger proportion of brain demyelination than white matter (WM) lesions. They are often missed on conventional MRI. Recently studies improved the detection of cortical lesions using 7T T2(⁎), 7T MPRAGE and 3T DIR but it seems that we are still able to detect only "the tip of the iceberg". In this study we report for the first time the systematic use of high resolution MTR in MS and compare MTR lesion detection with 7T MPRAGE, 7T T2(⁎) and 3T 3D DIR. OBJECTIVES: We report the use of high resolution, fast, magnetisation transfer imaging (MTI) at 7T in MS focusing on the detection of cortical lesions. SUBJECTS AND METHODS: Eighteen patients with MS were scanned (Expanded Disability Status Scale score: 3.0, mean age: 48 years, mean disease duration: 7.25 years). The scans were compared to nine healthy control subjects (mean age 36.5 years). DATA ACQUISITION: We acquired 7T MPRAGE images, 7T MTR maps, 7T T2(⁎)and 3T 3D DIR. The WM was segmented from the MPRAGE and removed to obtain only the cortical grey matter ribbon (cGMR) mask. The mask was then applied to the different modalities (MPRAGE, MTR, DIR, T2(⁎)w) previously registered onto the MPRAGE volume. The analysis of the cGMR was performed by two observers blinded to the disease state. RESULTS: In patients with MS 365 lesions in total were detected with 7T MTR (mean 20.28 lesions per patient), 289 lesions were detected with 7T MPRAGE (mean 16.06 lesions) and 231 lesions were detected with 7T T2(⁎) (mean 12.83 lesions). In the 8 MS subjects who had 3T 3D DIR acquired on the same day, a total of 136 lesions (mean 17 lesions per patient) were detected as opposed to 171 lesions with 7T MTR, 147 lesions were detected with 7T MPRAGE and 126 lesions with 7T T2(⁎) in the same patients. CONCLUSION: We found that 7T MTR, in less than 10min scanning time, was able to detect cortical lesions. In this study we found that 7T MTR was better in detecting intracortical lesions in comparison with 7T T2(⁎), 7T MPRAGE, and 3T 3D DIR. since only a very few intracortical lesions were detected in healthy controls in our blind assessment, it is likely that the lesions detected represent focal grey matter demyelination. High resolution MT imaging has especially revealed cortical changes that have not been recognised by other MR sequences. MTR maps were noisier than MPRAGE, T2(⁎) and DIR, but also better in localising cortical lesions. As MTR is more pathologically specific than other sequences in detecting tissue myelination, it raises the possibility that high resolution MTR will be able to demonstrate cortical remyelination in vivo.

A three dimensional drive system for use with fillable emission phantoms for SPECT and PET imaging.

Respiratory motion artefacts pose significant challenges for imaging of the lung and thorax. Dynamic phantoms have previously been applied to the study of respiratory motion, however, most moving platforms have been capable of movement in either one or two dimensions only. We describe a moving platform suitable for SPECT-CT and PET-CT imaging. The platform allows a fillable emission phantom to simulate rigid motion in three dimensions. Elliptical periodical motion of 1.5 cm in all three orthogonal planes was simulated using a series of cams moving a baseplate up and across a slope of 45°. The frequency of movement can be varied manually between 5 and 25 cycles per minute in a known calibrated and reproducible manner (This encompasses the range of physiological respiratory motion). Preliminary studies demonstrated that the phantom can be used to identify motion parameters and for the qualitative assessment of motion blurring in reconstructed images.

Sexual dimorphism in the adolescent brain: Role of testosterone and androgen receptor in global and local volumes of grey and white matter.

Here we examined sex differences in the volumes of grey and white matter, and in grey-matter "density," in a group of typically developing adolescents participating in the Saguenay Youth Study (n=419; 12-18 years). In male adolescents, we also investigated the role of a functional polymorphism in androgen-receptor gene (AR) in moderating the effect of testosterone on volumes of grey and white matter and grey-matter density. Overall, both absolute and relative volumes of white matter were larger in male vs. females adolescents. The relative grey-matter volumes were slightly larger in female than male adolescents and so was the grey-matter density in a large number of cortical regions. In male adolescents, functional polymorphism of AR moderated the effect of testosterone on relative white- and grey-matter volumes. Following a discussion of several methodological and interpretational issues, we outline future directions in investigating brain-behavior relationships vis-à-vis psychopathology.

Magnetization transfer phenomenon in the human brain at 7 T.

Magnetization transfer is an important source of contrast in magnetic resonance imaging which is sensitive to the concentration of macromolecules and other solutes present in the tissue. Magnetization transfer effects can be visualized in magnetization transfer ratio images or quantified via the z-spectrum. This paper presents methods of measuring the z-spectrum and of producing high-resolution MTR images and maps of z-spectrum asymmetry in vivo at 7 T, within SAR limits. It also uses a 3-compartment model to measure chemical exchange and magnetization transfer parameters from the z-spectrum data. The peak in the z-spectrum associated with chemical exchange between amide and water protons (amide proton transfer, APT, effects) is much more apparent at 7 T than at 3 T. Furthermore at 7 T quantitative APT results varied between the corpus callosum and other white matter structures, suggesting that quantitative APT imaging could be used as a method of measuring myelination. The results also suggest that chemical exchange is not responsible for the phase shift observed in susceptibility weighted images between grey matter and white matter.

Sex differences in the growth of white matter during adolescence.

The purpose of this study was to examine sex differences in the maturation of white matter during adolescence (12 to 18 years of age). We measured lobular volumes of white matter and white-matter "density" throughout the brain using T1-weighted images, and estimated the myelination index using magnetisation-transfer ratio (MTR). In male adolescents, we observed age-related increases in white-matter lobular volumes accompanied by decreases in the lobular values of white-matter MTR. White-matter density in the putative cortico-spinal tract (pCST) decreased with age. In female adolescents, on the other hand, we found only small age-related increase in white-matter volumes and no age-related changes in white-matter MTR, with the exception of the frontal lobe where MTR increased. White-matter density in the pCST also increased with age. These results suggest that sex-specific mechanisms may underlie the growth of white matter during adolescence. We speculate that these mechanisms involve primarily age-related increases in axonal calibre in males and increased myelination in females.

Corpus callosum in adolescent offspring exposed prenatally to maternal cigarette smoking.

Teratogens, such as alcohol or anti-epileptic drugs, affect the size of the corpus callosum. Here we report findings obtained in a case-control study that investigated possible effects of teratogens contained in cigarette smoke on the size and structural properties of this structure. We recruited and scanned with magnetic resonance imaging a total of 408 adolescents (12 to 18 years of age); a subsample of 300 adolescents is considered in this report. Cases (n=146) were exposed to maternal cigarette smoking during pregnancy; non-exposed controls (n=154) were matched to cases by maternal education. We measured the size of corpus callosum (CC) and its sections (corrected for brain size), as well as mean values of magnetization-transfer ratio (MTR) in each CC section. Corpus callosum, and especially its posterior part, was smaller in the exposed vs. non-exposed female adolescents; no significant effects were found in males. Exposed and non-exposed subjects did not differ in the MTR-based index of myelination in either gender in any CC section. Given the lack of exposure effect on the myelination index, this finding might reflect a lower number of inter-hemispheric connections in female offspring of mothers who smoked during pregnancy.

A myelo-architectonic method for the structural classification of cortical areas.

We describe an automatic and reproducible method to analyze the histological design of the cerebral cortex as applied to brain sections stained to reveal myelinated fibers. The technique provides an evaluation of the distribution of myelination across the width of the cortical mantle in accordance with a model of its curvature and its intrinsic geometry. The profile lines along which the density of staining is measured are generated from the solution of a partial differential equation (PDE) that models the intermediate layers of the cortex. Cortical profiles are classified according to significant components that emerge from wavelet analysis. Intensity profiles belonging to each distinct class are normalized and averaged to produce area-specific templates of cortical myelo-architecture.