Peculiar CADASIL phenotype in monozygotic twins carrying a novel NOTCH3 pathogenetic variant.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited cerebral small vessel disease caused by Neurogenic locus notch homolog protein 3 (NOTCH3) gene mutations. The main clinical features include migraine with aura, recurrent ischemic strokes and dementia. Brain MRI typically shows multiple small lacunar infarcts and severe, diffuse, symmetrical white matter hyperintensities (WMHs), with characteristic involvement of the anterior temporal pole, external capsule, and superior frontal gyrus. Reports of twins with CADASIL are scarce. Herein we describe a pair of monozygotic twins with peculiar CADASIL phenotype, carrying a new NOTCH3 variant. CASE PRESENTATION: Twin A was a 45-year-old male suffering from migraine, obesity, arterial hypertension, and polycythemia (with negative genetic analysis), who complained of a transient, short-lasting (~ 5 minutes) episode of speech difficulties. Brain MRI showed diffuse, symmetrical, confluent periventricular WMHs involving frontal, parietal, and temporal lobes and external capsules, with sparing of anterior temporal poles. Genetic analysis of NOTCH3 gene demonstrated the presence of missense c.3329G>A, p.(Cys1110Tyr) variant, confirming CADASIL diagnosis. Twin B, affected by migraine and polycythemia, as well as his monozygotic twin, presented with a 2-month history of trigeminal neuralgia. Brain MRI demonstrated diffuse WMHs with a pattern of distribution like his twin. Genetic analysis revealed the same NOTCH3 pathogenic variant. CONCLUSIONS: Our monozygotic twins have a strikingly similar neuroimaging picture with sparing of anterior temporal poles. They also have a peculiar phenotype, both presenting polycythemia without genetically confirmed cause. Twin B had trigeminal neuralgia, that is unusual in CADASIL. The possible association of the peculiar findings with the newly reported NOTCH3 variant needs to be confirmed with further observations.

Automatic quantification of multi-modal rigid registration accuracy using feature detectors.

In radiotherapy, the use of multi-modal images can improve tumor and target volume delineation. Images acquired at different times by different modalities need to be aligned into a single coordinate system by 3D/3D registration. State of the art methods for validation of registration are visual inspection by experts and fiducial-based evaluation. Visual inspection is a qualitative, subjective measure, while fiducial markers sometimes suffer from limited clinical acceptance. In this paper we present an automatic, non-invasive method for assessing the quality of intensity-based multi-modal rigid registration using feature detectors. After registration, interest points are identified on both image data sets using either speeded-up robust features or Harris feature detectors. The quality of the registration is defined by the mean Euclidean distance between matching interest point pairs. The method was evaluated on three multi-modal datasets: an ex vivo porcine skull (CT, CBCT, MR), seven in vivo brain cases (CT, MR) and 25 in vivo lung cases (CT, CBCT). Both a qualitative (visual inspection by radiation oncologist) and a quantitative (mean target registration error-mTRE-based on selected markers) method were employed. In the porcine skull dataset, the manual and Harris detectors give comparable results but both overestimated the gold standard mTRE based on fiducial markers. For instance, for CT-MR-T1 registration, the mTREman (based on manually annotated landmarks) was 2.2 mm whereas mTREHarris (based on landmarks found by the Harris detector) was 4.1 mm, and mTRESURF (based on landmarks found by the SURF detector) was 8 mm. In lung cases, the difference between mTREman and mTREHarris was less than 1 mm, while the difference between mTREman and mTRESURF was up to 3 mm. The Harris detector performed better than the SURF detector with a resulting estimated registration error close to the gold standard. Therefore the Harris detector was shown to be the more suitable method to automatically quantify the geometric accuracy of multimodal rigid registration.

Navigating toward a novel environment from a route or survey perspective: neural correlates and context-dependent connectivity.

When we move toward a novel environment we may learn it in different ways, i.e., by walking around or studying a map. Both types of learning seem to be very effective in daily life navigation and correspond to two different types of mental representation of space: route and survey representation. In the present study, we investigated the neural basis of route and survey perspectives during learning and retrieval of novel environments. The study was carried out over 5 days, during which participants learned two paths from a different perspective (i.e., route learning and survey learning). Then participants had to retrieve these paths using a survey or route perspective during fMRI scans, on the first and fifth day. We found that the left inferior temporal lobe and right angular gyrus (AG) were activated more during recall of paths learned in a survey perspective than in a route perspective. We also found a session by perspective interaction effect on neural activity in brain areas classically involved in navigation such as the parahippocampal place area (PPA) and the retrosplenial cortex (RSC). A set of frontal, parietal and temporal areas showed different patterns of activity according to the type of retrieval perspective. We tested the context-dependent connectivity of right PPA, RSC and AG, finding that these areas showed different patterns of connectivity in relation to the learning and recalling perspective. Our results shed more light on the segregation of neural circuits involved in the acquisition of a novel environment and navigational strategies.

The Corticospinal Tract in Huntington's Disease.

Huntington's disease (HD) is characterized by progressive motor impairment. Therefore, the connectivity of the corticospinal tract (CST), which is the main white matter (WM) pathway that conducts motor impulses from the primary motor cortex to the spinal cord, merits particular attention. WM abnormalities have already been shown in presymptomatic (Pre-HD) and symptomatic HD subjects using magnetic resonance imaging (MRI). In the present study, we examined CST microstructure using diffusion tensor imaging (DTI)-based tractography in 30-direction DTI data collected from 100 subjects: Pre-HD subjects (n = 25), HD patients (n = 25) and control subjects (n = 50), and T2*-weighted (iron sensitive) imaging. Results show decreased fractional anisotropy (FA) and increased axial (AD), and radial diffusivity (RD) in the bilateral CST of HD patients. Pre-HD subjects had elevated iron in the left CST, regionally localized between the brainstem and thalamus. CAG repeat length in conjunction with age, as well as motor (UHDRS) assessment were correlated with CST FA, AD, and RD both in Pre-HD and HD. In the presymptomatic phase, increased iron in the inferior portion supports the "dying back" hypothesis that axonal damage advances in a retrograde fashion. Furthermore, early iron alteration may cause a high level of toxicity, which may contribute to further damage.

MRI measures of corpus callosum iron and myelin in early Huntington's disease.

Increased iron in subcortical gray matter (GM) structures of patients with Huntington's disease (HD) has been suggested as a causal factor in neuronal degeneration. But how iron content is related to white matter (WM) changes in HD is still unknown. For example, it is not clear whether WM changes share the same physiopathology (i.e. iron accumulation) with GM or whether there is a different mechanism. The present study used MRI to examine iron content in premanifest gene carriers (PreHD, n = 25) and in early HD patients (n = 25) compared with healthy controls (n = 50). 3T MRI acquisitions included high resolution 3D T1, EPI sequences for diffusion tensor imaging (DTI) as an indirect measure of tissue integrity, and T2*-weighted gradient echo-planar imaging for MR-based relaxometry (R2*), which provides an indirect measure of ferritin/iron deposition in the brain. Myelin breakdown starts in the PreHD stage, but there is no difference in iron content values. Iron content reduction manifests later, in the early HD stage, in which we found a lower R2* parameter value in the isthmus. The WM iron reduction in HD is temporally well-defined (no iron differences in PreHD subjects and iron differences only in early HD patients). Iron level in callosal WM may be regarded as a marker of disease state, as iron does not differentiate PreHD subjects from controls but distinguishes between PreHD and HD.

Pharmacological therapies in post stroke recovery: recommendations for future clinical trials.

Stroke is a leading cause of serious long-term disability in adults and is the second leading cause of death worldwide. Early reperfusion and neuroprotection techniques have been the focus of much effort with the aim of very acute treatment of the stroke. Targeting different mechanisms, pharmacological therapies have the potential to reduce disability in a large fraction of patients who survive the acute stroke. The brain's capacity to reorganize after stroke through plasticity mechanisms can be modulated by pharmacological agents. A number of therapeutic interventions are under study, including small molecules, growth factors, and monoclonal antibodies. Recently it has been shown that the SSRI fluoxetine improved motor deficit in patients with ischaemic stroke and hemiplegia which appeared to be independent of the presence of depression. In this context, it is of major importance to support innovative research in order to promote the emergence of new pharmacological treatments targeting neurological recovery after stroke, as opposed to acute de-occlusion and neuroprotection. This paper is the work of a group of 14 scientists with aim of (1) addressing key areas of the basic and clinical aspects of human brain plasticity after stroke and potential pharmacological targets for recovery, (2) asking questions about the most appropriate characteristics of clinical trials testing drugs in post stroke recovery and (3) proposing recommendations for future clinical trials.

Effect of levodopa on both verbal and motor representations of action in Parkinson's disease: a fMRI study.

Previous studies have demonstrated that non-demented Parkinson's disease (PD) patients have a specific impairment of verb production compared with noun generation. One interpretation of this deficit suggested the influence of striato-frontal dysfunction on action-related verb processing. The aim of our study was to investigate cerebral changes after motor improvement due to dopaminergic medication on the neural circuitry supporting action representation in the brain as mediated by verb generation and motor imagery in PD patients. Functional magnetic resonance imaging on 8 PD patients in "ON" dopaminergic treatment state (DTS) and in "OFF" DTS was used to explore the brain activity during three different tasks: Object Naming (ObjN), Generation of Action Verbs (GenA) in which patients were asked to overtly say an action associated with a picture and mental simulation of action (MSoA) was investigated by asking subjects to mentally simulate an action related to a depicted object. The distribution of brain activities associated with these tasks whatever DTS was very similar to results of previous studies. The results showed that brain activity related to semantics of action is modified by dopaminergic treatment in PD patients. This cerebral reorganisation concerns mainly motor and premotor cortex suggesting an involvement of the putaminal motor loop according to the "motor" theory of verb processing.

Multimodal MRI analysis of the corpus callosum reveals white matter differences in presymptomatic and early Huntington's disease.

Recent magnetic resonance imaging (MRI) studies suggest that abnormalities in Huntington's disease (HD) extend to white matter (WM) tracts in early HD and even in presymptomatic stages. Thus, changes of the corpus callosum (CC) may reflect various aspects of HD pathogenesis. We recruited 17 HD patients, 17 pre-HD subjects, and 34 healthy age-matched controls. Three-dimensional anatomical MRI and diffusion tensor images of the brain were acquired on a 3T scanner. Combining region-of-interest analyses, voxel-based morphometry, and tract-based spatial statistics, we investigated callosal thickness, WM density, fractional anisotropy, and radial and axial diffusivities. Compared with controls, pre-HD subjects showed reductions of the isthmus, likely due to myelin damage. Compared with pre-HD subjects, HD patients showed reductions of isthmus and body, with axonal damage confined to the body. Compared with controls, HD patients had significantly decreased callosal measures in extended regions across almost the entire CC. At this disease stage, both myelin and axonal damage are detectable. Supplementary multiple regression analyses revealed that WM reduction density in the isthmus as well as Disease Burden scores allowed to predict the "HD development" index. While callosal changes seem to proceed in a posterior-to-anterior direction as the diseases progresses, this observation requires validation in future longitudinal investigations.

Developmental topographical disorientation in a healthy subject.

We present the case of F.G., a healthy, normally developed 22-year-old male subject affected by a pervasive disorder in environmental orientation and navigation who presents no history of neurological or psychiatric disease. A neuro-radiological examination showed no evidence of anatomical or structural alterations to the brain. We submitted the subject for a comprehensive neuropsychological assessment of the different cognitive processes involved in topographical orientation to evaluate his ability to navigate the spatial environment. The results confirmed a severe developmental topographical disorder and deficits in a number of specific cognitive processes directly or indirectly involved in navigation. The results are discussed with reference to the sole previously described case of developmental topographical disorientation (Pt1; Iaria et al., 2009). F.G. differs from the former case due to the following: the greater severity of his disorder, his complete lack of navigational skills, the failure to develop compensatory strategies, and the presence of a specific deficit in processing the spatial relationships between the parts of a whole. The present case not only confirms the existence of developmental topographical-skill disorders, but also sheds light on the architecture of topographical processes and their development in human beings.

User interface of a teleradiology system for the MR assessment of multiple sclerosis.

The aim of this study was to assess the image display of a web-based teleradiology system that uses a common web browser and has no need of proprietary applets, plug-ins, or dedicated software for DICOM display. The teleradiology system (TS) is connected to the Internet by ADSL and to radiological modalities using the DICOM standard with TCP/IP. Images were displayed on a PC through Internet connection with the remote TS using a common web browser. MS lesion number and volume in T1- and T2-weighted images (T1w and T2w, respectively) of 30 brain MR studies were quantified using both the TS and a conventional software. Wilcoxon signed ranks test and intraclass correlation coefficient (ICC) were used to assess the variability and concordance between intra- and inter-observer and TS and conventional DICOM viewer, setting significance at p < 0.05. No significant differences in T1w and T2w volumes between the TS and the conventional software were found by either operator. The ICC results showed a high level of inter-operator agreement in volume estimation in T1w and T2w images using the two systems. Quantitative assessment of MS lesion volumes in T1w and T2w images with a user interface of a teleradiology system that allows the consultation by means of a common web browser, without the need for proprietary plug-ins, applets, or dedicated software for DICOM display showed no significant differences from, and almost complete agreement with, conventional DICOM viewers.

Infratentorial lesion volume correlates with sensory functional system in multiple sclerosis patients: a 3.0-Tesla MRI study.

PURPOSE: This study sought to correlate lesion volume in infratentorial areas using 3.0-T proton-density (PD)-weighted images with disability scales and appropriate functional system scores in patients with multiple sclerosis (MS). MATERIALS AND METHODS: We examined 20 consecutive patients (13 women and 7 men) with a median age of 47 years (range 26-70). Neurological examination included the Expanded Disability Status Scale and its functional systems, the Barthel Index (BI) and the Rivermead Mobility Index (RMI). MRI scans were performed on a system operating at 3.0 T using a quadrature birdcage head coil. Acquired images imported as Digital Imaging and Communication in Medicine (DICOM) files, and the region of interest (ROI) files were converted to Neuroimaging Informatics Technology Initiative (NIfTI) format and normalised to the Montreal Neurological Institute (MNI) standard template. An automated segmentation algorithm was used to distinguish between supratentorial and infratentorial areas. Normalisation to the magnetisation-prepared rapid acquisition with gradient echo (MPRAGE) T1-weighted sequence allowed lesion volume estimation in the different anatomical areas. RESULTS: A significant correlation was found between infratentorial lesion volume and the sensory functional system score (rho=0.76, p=0.002). No significant correlation was found between supratentorial lesion volume and Expanded Disability Status Scale (EDSS), RMI and BI scores. CONCLUSIONS: The described method, by means of anatomical assignment of MS lesions, allows detection of significant correlation coefficients between clinical and MRI lesion burden in MS patients at the infratentorial level.

Reduced oxygen due to high-altitude exposure relates to atrophy in motor-function brain areas.

BACKGROUND AND PURPOSE: At high altitudes barometric pressure is reduced and, thus, less oxygen is inhaled. Reduced oxygen concentration in brain tissue can lead to cerebral damage and neurological and cognitive deficits. The present study was designed to explore the effects of high-altitude exposure using a quantitative MRI technique, voxel-based morphometry. METHODS: We studied nine world-class mountain climbers before (baseline) and after (follow-up) an extremely high-altitude ascent of Everest and K2. We investigated the effects of repeated extremely high-altitude exposures by comparing mountain climbers' scans at baseline with scans of 19 controls. In addition, we measured the effects of a single extremely high-altitude expedition by comparing mountain climbers' scans at baseline and follow-up. RESULTS: A region of reduced white matter density/volume was found in the left pyramidal tract near the primary (BA 4) and supplementary (BA 6) motor cortex when mountain climbers at baseline were compared with controls. Further, when mountain climbers' scans before and after the expedition were compared, a region of reduced grey matter density/volume was found in the left angular gyrus (BA 39). CONCLUSION: These findings suggest that extremely high-altitude exposures may cause subtle white and grey matter changes that mainly affect brain regions involved in motor activity.

Hippocampal atrophy is the critical brain change in patients with hypoxic amnesia.

Anoxia is considered a good model for studying amnesia. However, not all individuals who experience anoxic events develop memory problems. Moreover, the question still remains about whether, after anoxia, damage is limited to the hippocampus in patients with amnesia and without other significant cognitive deficits. Here we investigated brain damage in a selected sample of adults affected exclusively by an amnesic syndrome after an anoxic episode. The cerebral MR images of these patients were submitted to visual inspection, volumetric measurements of the mesial temporal structures following manual segmentation, and to Voxel-Based Morphometry of the whole brain. We studied five anoxic patients and thirty-three well-matched healthy subjects. Our aim was to: (a) quantify regional atrophic changes associated with chronic anoxic damage compared to control subjects (Group Comparison Analysis); (b) identify regions of common abnormality across all patients (Conjunction Analysis in the VBM); (c) investigate whether measures of regional volume reduction correlated with neuropsychological memory scores; (d) compare the results obtained with visual inspection and ROI analyses with those obtained with VBM. We found that anoxic patients presented a significant reduction of gray matter volume in the hippocampus bilaterally compared to healthy subjects. The only common atrophic region across all patients was the hippocampus bilaterally. Correlation analysis showed only a trend between the Prose immediate free recall test and the left hippocampus. Our findings confirm that the hippocampus is very sensitive to damage stemming from anoxia. Patients with hypoxic amnesia may present damage in other brain regions, but only hippocampal atrophy is common in all of them.

Imaging nervous pathways with MR tractography.

This paper describes the state of the art of tractography, a technique which enables the virtual reconstruction of axon bundles of the central nervous system using diffusion-weighted magnetic resonance images. This technique has raised enthusiasm and expectations among specialists because it is the only non-invasive method for studying the three-dimensional architecture of axonal fibres in vivo. Tractography is a new technique used to assess the anatomy of the central nervous system, and it will be available for routine clinical use in the future. Understanding its potential applications and limitations is therefore important.

Turbo-Proton Echo Planar Spectroscopic Imaging (t-PEPSI) MR technique in the detection of diffuse axonal damage in brain injury. Comparison with Gradient-Recalled Echo (GRE) sequence.

PURPOSE: Diffuse axonal injury (DAI) is a common type of primary neuronal injury in patients with severe traumatic brain injury, and is frequently accompanied by tissue tear haemorrhage. The T2*-weighted gradient-recalled echo (GRE) sequences are more sensitive than T2-weighted spin-echo images for detection of haemorrhage. This study was undertaken to determine whether turbo-PEPSI, an extremely fast multi-echo-planar-imaging sequence, can be used as an alternative to the GRE sequence for detection of DAI. MATERIALS AND METHODS: Nineteen patients (mean age 24,5 year) with severe traumatic brain injury (TBI), occurred at least 3 months earlier, underwent a brain MRI study on a 1.5-Tesla scanner. A qualitative evaluation of the turbo-PEPSI sequences was performed by identifying the optimal echo time and in-plane resolution. The number and size of DAI lesions, as well as the signal intensity contrast ratio (SI CR), were computed for each set of GRE and turbo-PEPSI images, and divided according to their anatomic location into lobar and/or deep brain. RESULTS: There was no significant difference between GRE and turbo-PEPSI sequences in the total number of DAI lesions detected (283 vs 225 lesions, respectively). The GRE sequence identified a greater number of hypointense lesions in the temporal lobe compared to the t-PEPSI sequence (72 vs 35, p<0.003), while no significant differences were found for the other brain regions. The SI CR was significantly better (i.e. lower) for the turbo-PEPSI than for the GRE sequence (p<0.00001). CONCLUSIONS: Owing to its very short scan time and high sensitivity to the haemorrhage foci, the turbo-PEPSI sequence can be used as an alternative to the GRE to assess brain DAI in severe TBI patients, especially if uncooperative and medically unstable.

Abnormal motor preparation in severe traumatic brain injury with good recovery.

Movement-related cortical potentials (MRCPs) were examined in seven patients with severe traumatic brain injury (TBI) and 12 matched control subjects. All patients had clinically established good recovery by the time of testing. Flexion movements of the index finger of the left or right hand were recorded in two (alternating and repetitive) self-paced conditions and in one externally triggered condition. In control subjects, the bereitschaftspotential (BP) component of MRCP was detected approximately 2000 msec prior to movement onset in the self-paced conditions and was larger and earlier in the alternating compared to the repetitive condition. The BP component was absent in the externally triggered condition. In TBI patients, the BP was greatly reduced and no difference between the alternating-repetitive conditions was detected; in contrast, only small differences were present in the controls for the negative slope (NS) and MP components and no difference for the reafferent positivity (RAP) component. A dipole analysis indicated the supplementary motor area and the premotor area as the likely generators of BP and NS' components, respectively. Gradientrecalled echo magnetic resonance imaging allowed the detection of a number of small hypointense lesions primarily located in the frontal lobes, as in diffuse axonal injury. This pattern of results indicates a selective deficit in motor preparation and a relatively spared pattern of activation during and following movement in these patients. Imaging data appear generally consistent with the pattern of MRCPs observed in the patient group. Implications of these results for the problem of slowness in TBI patients are discussed.

Atypical multiple sclerosis: MRI findings and differential diagnosis.

In the past few years, magnetic resonance imaging (MRI) has become increasingly relevant in the diagnosis of multiple sclerosis (MS). Yet, the specificity of MR is limited. Atypical forms of MS and other diseases of the central nervous system may show similar patterns in MR. We briefly discuss the MR findings of the main MS-like diseases. Correct differential diagnosis can be carried out by combining the MR findings with clinical and laboratory findings.

Diffusion of water in large demyelinating lesions: a follow-up study.

We studied five patients with multiple sclerosis with one plaque of demyelination more than 2 cm in diameter, using conventional and diffusion-weighted MRI, soon after the onset of symptoms and over 1-36 months. The orientationally averaged diffusion coefficient was increased in all the acute lesions, and increased further during follow-up in three. There was a strong correlation between and the degree of low signal on T1-weighted images. The quantitative information provided by allowed delineation of different diffusion patterns in large MS lesions, that may reflect heterogeneity of the anatomical substrate.