Neuroanatomical patterns of cerebral white matter involvement in different motor neuron diseases as studied by diffusion tensor imaging analysis.

This study was designed to investigate differences of white matter (WM) involvement patterns in various motor neuron disorders (MND) by use of diffusion tensor imaging (DTI).DTI was acquired in ALS (n = 20), primary lateral sclerosis (n = 20), pure hereditary spastic paraparesis (HSP) (n = 20), and complicated HSP (n = 12). The data analysis was performed by voxelwise comparison of fractional anisotropy (FA) maps at group level together with fibre tracking in regions of interest (ROI) accompanied by tractwise fractional anisotropy statistics. DTI analysis revealed widespread patterns of alterations with a predominant deterioration of the motor system. These alterations encompassed, as the key structures, not only the corticospinal tracts (CST) but also distinct areas of the corpus callosum (CC), in particular its motor segment III. In conclusion, whole brain-based and tract-based DTI analysis was able to define a distinct WM pathoanatomy of different MND. These results may serve as an additional guidance in the identification of MRI-based parameters by showing a consistent CST and CC involvement, with differences in the extent of pathology, across a range of clinically different disorders. For potential future developments in MRI diagnostics in MND, a (perhaps multiparametric) ROI-based approach should include CST and the CC motor segment.

The cerebro-morphological fingerprint of a progeroid syndrome: white matter changes correlate with neurological symptoms in xeroderma pigmentosum.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive progeroid syndrome. It has recently been shown that the underlying DNA repair defect plays a central role in the aging process. In addition to skin symptoms, various premature neurological abnormalities have been reported. METHODOLOGY/PRINCIPAL FINDINGS: We present the clinical neurological phenotype in 14 XP patients (seven subtypes), in seven of these patients together with conventional and multiparametric advanced MRI data to assess the macrostructural and microstructural cerebral morphology in comparison to controls, including volumetric measurements, MR spectroscopy ((1)H MRS), and diffusion tensor imaging (DTI). Clinical hallmarks were spinocerebellar ataxia, pyramidal tract signs, and mild cognitive deficits. DTI demonstrated significantly reduced WM directionality in all regions investigated, i.e. the thalamus, the corticospinal tracts and the dorsal corpus callosum. Single patients showed a marked relative hippocampal volume reduction, but the patients were not different from controls in the volumetric measurements of hippocampal and whole brain volumes at group level. However, (1)H MRS demonstrated that the hippocampal formation was metabolically altered. CONCLUSIONS: The most prominent feature was the white matter affectation, as assessed by DTI, with volume and directionality reductions of the fiber projections involving both the craniocaudal fibers and the interhemispheric connections. These findings, although heterogeneous among the study sample, could be correlated with the clinico-neurological symptoms. The imaging findings support the position that myelin structures degrade prematurely in the brain of XP patients.

Slowly progressive Foix-Chavany-Marie syndrome as a precursor of a primary progressive aphasia.

Foix-Chavany-Marie syndrome (FCMS) is a rare neurological condition usually associated with bilateral ischemic lesions of the anterior frontoparietal operculum. Here, we present a patient with slowly progressive FCMS owing to focal brain atrophy who developed a language disorder similar to that seen in a primary progressive aphasia.

Long-term outcome in transient global amnesia patients with and without focal hyperintensities in the CA1 region of the hippocampus.

Focal hippocampal diffusion-weighted imaging (DWI) lesion patterns are detected in transient global amnesia (TGA) patients in different frequency. It has been speculated that acute diffusion restrictions are associated with a worse outcome. Therefore, we evaluated the influence of acute DWI lesions on the cognitive long-term outcome in TGA patients. Seventeen otherwise healthy patients with the clinical syndrome of TGA, who had MRI investigations on admission as well as 1 day later, were investigated with a comprehensive neuropsychological test battery 2 years later. Acute hippocampal DWI lesions in TGA patients were detected in almost two thirds of the patients. Psychometric evaluation revealed no differences in cognitive performance between patients with and without DWI lesions as well as compared to healthy subjects. In addition, no relapse of the attack has been recognized in either group of TGA patients.

Signal alterations of the basal ganglia in the differential diagnosis of Parkinson's disease: a retrospective case-controlled MRI data bank analysis.

BACKGROUND: Based upon the acquainted loss of dopaminergic neurons in the substantia nigra in Parkinson's disease (PD), we hypothesised changes in magnetic resonance imaging signal intensities of the basal ganglia to be useful as an additional technical tool in the diagnostic work-up. METHODS: Region-of-interest analyses (substantia nigra and globus pallidus internus) of T2-weighted scans were performed in seventy subjects with PD, 170 age- and gender-matched controls and 38 patients with an atypical form of neurodegenerative Parkinsonian syndrome (N = 11 multisystem atrophy, N = 22 progressive supranuclear palsy, N = 5 corticobasal syndrome). RESULTS: In patients with PD, significant changes in signal intensities within the substantia nigra were observed compared to controls at p < 0.001. For the globus pallidus internus, signal alterations in PD and progressive supranuclear palsy were found to be significant (p < 0.001) if compared to controls. Furthermore, signal changes of substantia nigra correlated with signal intensities of globus pallidus internus in the ipsilateral hemisphere in both groups. Sensitivity was 86% and specificity was 90% for the combined analysis of substantia nigra and globus pallidus internus in the complete patient sample versus controls. CONCLUSIONS: Signal alterations of substantia nigra and globus pallidus internus in routine magnetic resonance imaging were useful to distinguish patients with PD from controls. In addition, signal changes in globus pallidus internus could be used to differentiate progressive supranuclear palsy patients from controls. These analyses have the potential to serve as an additional non-invasive technical tool to support the individual differential diagnosis of PD.

Stability of white matter changes related to Huntington's disease in the presence of imaging noise: a DTI study.

Movement artifacts and other sources of noise are a matter of concern particularly in the neuroimaging research of movement disorders such as Huntington's disease (HD). Using diffusion weighted imaging (DWI) and fractional anisotropy (FA) as a compound marker of white matter integrity, we investigated the effect of movement on HD specific changes in magnetic resonance imaging (MRI) data and how post hoc compensation for it affects the MRI results. To this end, we studied by 3T MRI: 18 early affected, 22 premanifest gene-positive subjects, 23 healthy controls (50 slices of 2.3 mm thickness per volume, 64 diffusion-weighted directions (b = 1000 s/mm2), 8 minimal diffusion-weighting (b = 100 s/mm2)); and by 1.5 T imaging: 29 premanifest HD, 30 controls (40 axial slices of 2.3 mm thickness per volume, 61 diffusion-weighted directions (b = 1000 s/mm2), minimal diffusion-weighting (b = 100 s/mm2)). An outlier based method was developed to identify movement and other sources of noise by comparing the index DWI direction against a weighted average computed from all other directions of the same subject. No significant differences were observed when separately comparing each group of patients with and without removal of DWI volumes that contained artifacts. In line with previous DWI-based studies, decreased FA in the corpus callosum and increased FA around the basal ganglia were observed when premanifest mutation carriers and early affected patients were compared with healthy controls. These findings demonstrate the robustness of the FA value in the presence of movement and thus encourage multi-center imaging studies in HD.

Patterns of TH1/TH2 cytokines predict clinical response in multiple sclerosis patients treated with glatiramer acetate.

The patterns of Th1/Th2 cytokines in relapsing-remitting multiple sclerosis were analyzed to evaluate their relevance as biomarkers of therapy response to glatiramer acetate (GA). Serum interferon-γ (IFN-γ), osteopontin and interleukin (IL)-2, IL-4, and IL-10 were measured in 19 relapsing-remitting multiple sclerosis patients treated with GA in a prospective study over 3 years. The quotient (IL-2 + IFN-γ)/(IL-4 + IL-10) was elevated in patients with relapses as compared to relapse-free patients after 12 (p = 0.04), 24 (p = 0.02) and 36 months (p = 0.04). Our study indicates that specific patterns of Th1/Th2 cytokines predict the response to GA therapy.

Complementary image analysis of diffusion tensor imaging and 3-dimensional t1-weighted imaging: white matter analysis in amyotrophic lateral sclerosis.

INTRODUCTION: in order to obtain detailed information on disease-associated changes in the integrity of cerebral white matter (WM), complementary image analysis (CIA) was applied to patients with amyotrophic lateral sclerosis (ALS) and controls. METHODS: both diffusion tensor imaging and T1-weighted 3-dimensional data were analyzed with respect to WM microstructure and T1 signal intensity alterations, respectively, in a sample of 19 ALS patients. Covariate information was added in the form of clinical parameters. All results were obtained in one common analysis software environment (Tensor Imaging and Fiber Tracking). RESULTS: complementary analysis and display were performed for WM directionality and structure. Significant WM differences between ALS patients and controls were observed both in the motor system, that is, the bilateral corticospinal tracts, and in extramotor brain areas, in part correlating with clinical parameters. The performance of all analyses in one software environment enabled the synopsis of results obtained from various analyses. DISCUSSION/CONCLUSION: within the application of CIA to a neurodegenerative disease for the whole brain-based analysis of WM alterations together with clinical characteristics, it could be demonstrated that ALS was associated with WM changes within and outside the motor system.

Quantification of human body fat tissue percentage by MRI.

The MRI-based evaluation of the quantity and regional distribution of adipose tissue is one objective measure in the investigation of obesity. The aim of this article was to report a comprehensive and automatic analytical method for the determination of the volumes of subcutaneous fat tissue (SFT) and visceral fat tissue (VFT) in either the whole human body or selected slices or regions of interest. Using an MRI protocol in an examination position that was convenient for volunteers and patients with severe diseases, 22 healthy subjects were examined. The software platform was able to merge MRI scans of several body regions acquired in separate acquisitions. Through a cascade of image processing steps, SFT and VFT volumes were calculated. Whole-body SFT and VFT distributions, as well as fat distributions of defined body slices, were analysed in detail. Complete three-dimensional datasets were analysed in a reproducible manner with as few operator-dependent interventions as possible. In order to determine the SFT volume, the ARTIS (Adapted Rendering for Tissue Intensity Segmentation) algorithm was introduced. The advantage of the ARTIS algorithm was the delineation of SFT volumes in regions in which standard region grow techniques fail. Using the ARTIS algorithm, an automatic SFT volume detection was feasible. MRI data analysis was able to determine SFT and VFT volume percentages using new analytical strategies. With the techniques described, it was possible to detect changes in SFT and VFT percentages of the whole body and selected regions. The techniques presented in this study are likely to be of use in obesity-related investigations, as well as in the examination of longitudinal changes in weight during various medical conditions.

Whole brain-based analysis of regional white matter tract alterations in rare motor neuron diseases by diffusion tensor imaging.

Different motor neuron disorders (MNDs) are mainly defined by the clinical presentation based on the predominance of upper or lower motor neuron impairment and the course of the disease. Magnetic resonance imaging (MRI) mostly serves as a tool to exclude other pathologies, but novel approaches such as diffusion tensor imaging (DTI) have begun to add information on the underlying pathophysiological processes of these disorders in vivo. The present study was designed to investigate three different rare MNDs, i.e., primary lateral sclerosis (PLS, N = 25), hereditary spastic paraparesis (HSP, N = 24), and X-linked spinobulbar muscular atrophy (X-SBMA, N = 20), by use of whole-brain-based DTI analysis in comparison with matched controls. This analysis of white matter (WM) impairment revealed widespread and characteristic patterns of alterations within the motor system with a predominant deterioration of the corticospinal tract (CST) in HSP and PLS patients according to the clinical presentation and also in patients with X-SBMA to a lesser degree, but also WM changes in projections to the limbic system and within distinct areas of the corpus callosum (CC), the latter both for HSP and PLS. In summary, DTI was able to define a characteristic WM pathoanatomy in motor and extra-motor brain areas, such as the CC and the limbic projectional system, for different MNDs via whole brain-based FA assessment and quantitative fiber tracking. Future advanced MRI-based investigations might help to provide a fingerprint-identification of MNDs.

At-risk for pathological gambling: imaging neural reward processing under chronic dopamine agonists.

Treatment with dopamine receptor agonists has been associated with impulse control disorders and pathological gambling (PG) secondary to medication in previously unaffected patients with Parkinson's disease or restless legs syndrome (RLS). In a within-subjects design, we investigated the underlying neurobiology in RLS patients using functional magnetic resonance imaging. We scanned 12 female RLS patients without a history of PG. All patients were scanned twice: once whilst taking their regular medication with low dose dopamine receptor agonists and once after a washout phase interval. They performed an established gambling game task involving expectation and receipt or omission of monetary rewards at different levels of probabilities. Upon expectation of rewards, reliable ventral striatal activation was detected only when patients were on, but not when patients were off medication. Upon receipt or omission of rewards, the observed ventral striatal signal under medication differed markedly from its predicted pattern which by contrast was apparent when patients were off medication. Orbitofrontal activation was not affected by medication. Chronic dopamine receptor agonist medication changed the neural signalling of reward expectation predisposing the dopaminergic reward system to mediate an increased appetitive drive. Even without manifest PG, chronic medication with dopamine receptor agonists led to markedly changed neural processing of negative consequences probably mediating dysfunctional learning of contingencies. Intact orbitofrontal functioning, potentially moderating impulse control, may explain why none of the patients actually developed PG. Our results support the notion of a general medication effect in patients under dopamine receptor agonists in terms of a sensitization towards impulse control disorders.

Histopathological analysis of skeletal muscle in patients with Parkinson's disease and 'dropped head'/'bent spine' syndrome.

BACKGROUND: 'Dropped head' and 'bent spine' phenomena are recognized clinical presentations of neuromuscular disorders. Similar symptoms are known in patients with parkinsonian syndromes, but their pathophysiology remains unclear. One hypothesis is a relation between the movement disorder and the skeletal muscle pathology. METHODS: We describe detailed histopathological data from 19 consecutive skeletal muscle biopsies in patients with idiopathic Parkinson's disease (PD) and concomitant 'dropped head' or 'bent spine' syndrome. A biochemical analysis of the respiratory chain complexes was also performed, and clinical, electrophysiological, and imaging data were analyzed. RESULTS: The subjects developed neuromuscular symptoms 2.7 +/- 2.4 years after onset of PD. We found no correlation with the age at onset of the disease, disease duration, or severity. We found no evidence for dystonia nor did we find any relationship between their anti-parkinsonian medication, and possible drug side effects. Muscle biopsies were abnormal in all patients. Based on histopathological criteria we divided the muscle pathology into three different groups, i.e. necrotizing myopathy, inflammatory myopathy, and myopathy with mitochondrial abnormalities. Biochemical analysis of respiratory chain complexes revealed abnormalities in nine patients. CONCLUSIONS: 'Dropped head' and 'bent spine' symptoms in association with PD appear to be accompanied by a wide spectrum of histopathological abnormalities in skeletal muscle. A muscle biopsy should be performed to identify potentially treatable conditions (i.e. inflammatory myopathies).

Dopamine Agonists and their risk to induce psychotic episodes in Parkinson's disease: a case-control study.

BACKGROUND: Psychosis is rare in untreated patients with Parkinson's disease (PD) but the prevalence rises to 40% during dopaminergic treatment. So far, no systematic comparison of the psychogenic potential of different dopaminergic drugs had been performed. METHODS: Eighty PD patients with psychotic episodes were compared to an age-matched control group of PD patients without psychotic episodes (n = 120) in a cross-sectional retrospective study. RESULTS: We found a positive correlation between psychotic episodes and dementia, number of concomitant medication, and pergolide intake. Odds ratio calculation confirmed the association with dementia. With respect to dopaminergic treatment, pergolide showed the highest odds ratio, levodopa the lowest. An adjusted logistic regression model confirmed the strong association with psychotic episodes and pergolide and no association with levodopa (adjusted odds ratio 2.01 and 0.11, respectively). CONCLUSION: The analysis indicates that dementia and concomitant medication are factors in PD associated with psychotic symptoms. Furthermore, different dopaminergic drugs showed markedly different associations with psychotic symptoms.

Intersubject variability in the analysis of diffusion tensor images at the group level: fractional anisotropy mapping and fiber tracking techniques.

INTRODUCTION: Diffusion tensor imaging (DTI) provides comprehensive information about quantitative diffusion and connectivity in the human brain. Transformation into stereotactic standard space is a prerequisite for group studies and requires thorough data processing to preserve directional inter-dependencies. The objective of the present study was to optimize technical approaches for this preservation of quantitative and directional information during spatial normalization in data analyses at the group level. METHODS: Different averaging methods for mean diffusion-weighted images containing DTI information were compared, i.e., region of interest-based fractional anisotropy (FA) mapping, fiber tracking (FT) and corresponding tractwise FA statistics (TFAS). The novel technique of intersubject FT that takes into account directional information of single data sets during the FT process was compared to standard FT techniques. Application of the methods was shown in the comparison of normal subjects and subjects with defined white matter pathology (alterations of the corpus callosum). RESULTS: Fiber tracking was applied to averaged data sets and showed similar results compared with FT on single subject data. The application of TFAS to averaged data showed averaged FA values around 0.4 for normal controls. The values were in the range of the standard deviation for averaged FA values for TFAS applied to single subject data. These results were independent of the applied averaging technique. A significant reduction of the averaged FA values was found in comparison to TFAS applied to data from subjects with defined white matter pathology (FA around 0.2). CONCLUSION: The applicability of FT techniques in the analysis of different subjects at the group level was demonstrated. Group comparisons as well as FT on group averaged data were shown to be feasible. The objective of this work was to identify the most appropriate method for intersubject averaging and group comparison which incorporates intersubject variability of the directional information.

Whole brain-based computerized neuroimaging in ALS and other motor neuron disorders.

Advanced neuroimaging applications to patients suffering from ALS and other motor neuron disorders (MND) have a high potential in terms of understanding the pathophysiology and visualizing the in vivo pathoanatomy of the diseases. In this context, particularly observer-independent computerized analyses of magnetic resonance imaging (MRI) data are of special interest since they overcome shortcomings of region-of-interest-based techniques. For three-dimensional structural T1-weighted MRI of the whole brain, voxel-based morphometry (VBM) has proven the most valuable approach to analyse regional volume alterations of the grey or white matter at group level. For the analysis of the white matter integrity with respect to tissue diffusivity and white matter connectivity including fibre tracking algorithms, diffusion tensor imaging (DTI) which can also be performed on a whole brain-basis is of the highest potential to date. Both VBM and DTI have been applied to various MND, in particular ALS, in multiple studies over recent years and have substantially broadened our knowledge about their in vivo pathoanatomy and mechanisms of neurodegeneration. Especially both the degree of damage to motor areas and the involvement of non-motor areas are of interest to be subjected to quantitative assessment, in order to establish quantitative surrogate markers for disease progression usable in clinical trials. Here, the technical state-of-the-art and the results of VBM and DTI studies in MND as the current state are reviewed, and future perspectives for further neuroimaging applications are highlighted.

Cerebral white matter alterations in idiopathic restless legs syndrome, as measured by diffusion tensor imaging.

In search for the pathoanatomical correlate of the restless legs syndrome (RLS), various neuroimaging and electrophysiological techniques have demonstrated partly conflicting results of cortical, subcortical, brainstem, and spinal alterations. In a novel approach, the delineation of potential cerebral white matter tract disruption was investigated by application of quantitative whole brain-based diffusion tensor imaging (DTI) to a well characterized group of 45 patients with idiopathic RLS. The data of patients and 30 healthy controls were statistically compared including computation of regional fractional anisotropy (FA) as a quantitative marker of white matter integrity by use of the tensor imaging and fiber tracking software. In the patient group, multiple subcortical areas of significantly reduced FA were observed bihemispherically in close proximity to the primary and associate motor and somatosensory cortices, in the right-hemispheric thalamus (posterior ventral lateral nucleus), in motor projectional fibers and adjacent to the left anterior cingulum. Together with the results of a recent study by use of an MRI-based gray matter analysis, which localized RLS-associated changes in the sensorimotor cortices, these findings gave support to an altered subcortical network, with the major component of altered cerebral sensorimotor pathways, within a hodological concept of the RLS pathoanatomy.

Directional colour encoding of the human thalamus by diffusion tensor imaging.

The potential of diffusion tensor imaging (DTI) in brain imaging in terms of the in vivo mapping of neuroanatomy is generally accepted. Mostly, analyses of deep brain structures were based on complex methodical backgrounds. In the present study, the delineation of groups of thalamic nuclei with similar projection characteristics was investigated in healthy human subjects using a novel differentiated colour encoding approach of DTI data without the use of statistical calculations. With the application of this directional colour encoding of the longest eigenvector of every voxel-specific tensor, at least three functional groups in the thalamus with different projection directions could be differentiated. The method displayed, furthermore, a high symmetry and stability in the analysis of the individual subjects. In summary, substantial neuroanatomical information can be gained for deep subcortical gray matter structures such as the thalamus with an improved detection and directional differentiation of voxel-specific tensors.

Diffusion tensor imaging and tractwise fractional anisotropy statistics: quantitative analysis in white matter pathology.

BACKGROUND: Information on anatomical connectivity in the brain by measurements of the diffusion of water in white matter tracts lead to quantification of local tract directionality and integrity. METHODS: The combination of connectivity mapping (fibre tracking, FT) with quantitative diffusion fractional anisotropy (FA) mapping resulted in the approach of results based on group-averaged data, named tractwise FA statistics (TFAS). The task of this study was to apply these methods to group-averaged data from different subjects to quantify differences between normal subjects and subjects with defined alterations of the corpus callosum (CC). RESULTS: TFAS exhibited a significant FA reduction especially in the CC, in agreement with region of interest (ROI)-based analyses. CONCLUSION: In summary, the applicability of the TFAS approach to diffusion tensor imaging studies of normal and pathologically altered brains was demonstrated.

Different regional brain volume loss in pure and complicated hereditary spastic paraparesis: a voxel-based morphometric study.

Three-dimensional magnetic resonance imaging of the brain was analyzed using optimized voxel-based morphometry in 21 patients with pure hereditary spastic paraparesis (pHSP) and 12 patients with complicated HSP (cHSP). PHSP patients showed only small regional grey matter volume reduction, whereas significantly decreased grey matter volumes were localized pericentrally in cHSP. In the white matter, several small areas of regional volume reduction were observed in the pHSP patients, whereas the cHSP group exhibited large robust volume reduction involving the entire corpus callosum, a result that was reproduced by an additional region-based MRI analysis. It could be demonstrated that the topography of cerebral volume changes differed markedly in pHSP or cHSP at group level. Corpus callosum thinning seems to be a general feature of cHSP.