Alexander Unrath

Global brain atrophy and corticospinal tract alterations in ALS, as investigated by voxel‐based morphometry of 3‐D MRI

In ALS, advanced magnetic resonance imaging (MRI) techniques are increasingly used to investigate the underlying pathology. In this study, the technique of voxel‐based morphometry (VBM) was applied to 3‐D MRI data in ALS patients to localize regional grey and white matter changes. Twenty‐two ALS patients (mean age 58±9 years) with clinically definite ALS by revised El Escorial criteria were studied. None of the patients had any signs of associated frontotemporal dementia. High‐resolution 3‐D MRI data sets of the whole brain, collected on a 1.5 T scanner, were analysed by statistical parametric mapping (SPM) and VBM in comparison to an age‐matched normal data base consisting of 22 healthy volunteers (mean age 59±11 years), for grey matter and white matter segments separately. Global brain atrophy was assessed by calculation of brain parenchymal fractions (BPF). In ALS patients, BPF were significantly reduced compared to controls (p = 0.0003), indicating global brain atrophy. Regional decreases of grey matter density were found in the ALS patients at corrected p<0.01 in the right‐hemispheric primary motor cortex (area of the highest Z‐score) and in the left medial frontal gyrus. Furthermore, regional white matter alterations were observed along the corticospinal tracts bilaterally and in multiple smaller areas including corpus callosum, cerebellum, frontal and occipital subcortical regions. Besides considerable global atrophy in ALS, the topography of ALS‐associated cerebral morphological changes could be mapped using VBM, in particular white matter signal changes along the bilateral corticospinal tracts, but also in extra‐motor areas. VBM might be a potential tool to visualize disease progression in future longitudinal studies.

Preservation of diffusion tensor properties during spatial normalization by use of tensor imaging and fibre tracking on a normal brain database

White matter connectivity in the human brain can be mapped by diffusion tensor magnetic resonance imaging (DTI). After reconstruction, the diffusion tensors, the diffusion amplitude and the diffusion direction can be displayed on a morphological background. Consequently, diffusion tensor fibre tracking can be applied as a non-invasive in vivo technique for the delineation and quantification of specific white matter pathways. The aim of this study was to show that normalization to the Montreal Neurological Institute (MNI) stereotaxic standard space preserves specific diffusion features. Therefore, techniques for tensor imaging and fibre tracking were applied to the normalized brains as well as to the group averaged brain data. A normalization step of individual data was included by registration to a scanner- and sequence-specific DTI template data set which was created from a normal database transformed to MNI space. The algorithms were tested and validated for a group of 13 healthy controls.

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 Parkinsons 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.

Cortical grey matter alterations in idiopathic restless legs syndrome: An optimized voxel-based morphometry study.

An impairment of central somatosensory processing is assumed in restless legs syndrome (RLS). Although functional neuroimaging in RLS gave evidence to the presence of widespread functional changes in various brain areas, structural changes at the cortical level were not reported to be RLS‐associated to date. Here, an analysis of high‐resolution three‐dimensional magnetic resonance imaging (MRI) was performed in 63 patients with idiopathic RLS by use of optimized voxel‐based morphometry, in order to investigate if cortical areas might be altered in volume at group level according to the phenomenology of RLS. The comparison of the RLS patients versus controls yielded significant regional decreases of gray matter volume at corrected P < 0.05 in the bihemispheric primary somatosensory cortex, which additionally extended into left‐sided primary motor areas. All clusters correlated both with the severity of RLS symptoms and with disease duration. These results, for the first time, give in vivo evidence to structural neocortical gray matter alterations in RLS patients. The alterations in the sensorimotor cortices might add to the pathophysiological concepts of idiopathic RLS.

Brain metabolites in definite amyotrophic lateral sclerosis. A longitudinal proton magnetic resonance spectroscopy study.

Biomarkers beyond clinical assessment are needed in patients who suffer from amyotrophic lateral sclerosis (ALS). Here, single-voxel proton magnetic resonance spectroscopy (1H MRS) of the gray matter of the motor cortex and the white matter including the pyramidal tracts was used to investigate concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol, glutamate, and glutamine in patients with definite ALS in a longitudinal design (three measurements at study inclusion, after 3 and 6 months). A volume-corrected analysis of gray and white matter fractions within the volumes of interest (VOI) was performed for the identification of the absolute metabolite concentrations. The patient group showed a significant decline of the compound NAA over time in the motor cortex areas both of the clinically more and less affected hemisphere between first measurement and month 6 and for the less affected side additionally between first measurement and month 3. For the NAA/(Cr + Cho) ratio, significant decline in the less affected hemisphere was observed from the first measurement to month 3 and to month 6 as well as from month 3 to month 6. In contrast, neither NAA nor the NAA/(Cr + Cho) ratios in the white matter areas showed any significant alterations. All other compounds showed no significant changes over time. In summary, the longitudinal changes of cortical metabolite concentrations in the course of ALS could be assessed by optimized 1H MRS techniques at group level, so that 1H MRS parameters, in particular volume-corrected values of NAA in the clinically less affected hemisphere, seem to have the potential to serve as a surrogate marker for monitoring ALS disease progression.

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

BackgroundPsychosis is rare in untreated patients with Parkinsons 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.MethodsEighty 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.ResultsWe 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).ConclusionThe 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

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.

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. Copyright

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

BackgroundInformation 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.MethodsThe 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).ResultsTFAS exhibited a significant FA reduction especially in the CC, in agreement with region of interest (ROI)-based analyses.ConclusionIn summary, the applicability of the TFAS approach to diffusion tensor imaging studies of normal and pathologically altered brains was demonstrated.

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

Abstract 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.