Julian Grosskreutz

Prefrontal and anterior cingulate cortex abnormalities in Tourette Syndrome: evidence from voxel-based morphometry and magnetization transfer imaging

BackgroundPathophysiological evidence suggests an involvement of fronto-striatal circuits in Tourette syndrome (TS). To identify TS related abnormalities in gray and white matter we used optimized voxel-based morphometry (VBM) and magnetization transfer imaging (MTI) which are more sensitive to tissue alterations than conventional MRI and provide a quantitative measure of macrostructural integrity.MethodsVolumetric high-resolution anatomical T1-weighted MRI and MTI were acquired in 19 adult, unmedicated male TS patients without co-morbidities and 20 age- and sex-matched controls on a 1.5 Tesla neuro-optimized GE scanner. Images were pre-processed and analyzed using an optimized version of VBM in SPM2.ResultsUsing VBM, TS patients showed significant decreases in gray matter volumes in prefrontal areas, the anterior cingulate gyrus, sensorimotor areas, left caudate nucleus and left postcentral gyrus. Decreases in white matter volumes were detected in the right inferior frontal gyrus, the left superior frontal gyrus and the anterior corpus callosum. Increases were found in the left middle frontal gyrus and left sensorimotor areas. In MTI, white matter reductions were seen in the right medial frontal gyrus, the inferior frontal gyrus bilaterally and the right cingulate gyrus. Tic severity was negatively correlated with orbitofrontal structures, the right cingulate gyrus and parts of the parietal-temporal-occipital association cortex bilaterally.ConclusionOur MRI in vivo neuropathological findings using two sensitive and unbiased techniques support the hypothesis that alterations in frontostriatal circuitries underlie TS pathology. We suggest that anomalous frontal lobe association and projection fiber bundles cause disinhibition of the cingulate gyrus and abnormal basal ganglia function.

A large-scale multicentre cerebral diffusion tensor imaging study in amyotrophic lateral sclerosis

Objective Damage to the cerebral tissue structural connectivity associated with amyotrophic lateral sclerosis (ALS), which extends beyond the motor pathways, can be visualised by diffusion tensor imaging (DTI). The effective translation of DTI metrics as biomarker requires its application across multiple MRI scanners and patient cohorts. A multicentre study was undertaken to assess structural connectivity in ALS within a large sample size. Methods 442 DTI data sets from patients with ALS (N=253) and controls (N=189) were collected for this retrospective study, from eight international ALS-specialist clinic sites. Equipment and DTI protocols varied across the centres. Fractional anisotropy (FA) maps of the control participants were used to establish correction matrices to pool data, and correction algorithms were applied to the FA maps of the control and ALS patient groups. Results Analysis of data pooled from all centres, using whole-brain-based statistical analysis of FA maps, confirmed the most significant alterations in the corticospinal tracts, and captured additional significant white matter tract changes in the frontal lobe, brainstem and hippocampal regions of the ALS group that coincided with postmortem neuropathological stages. Stratification of the ALS group for disease severity (ALS functional rating scale) confirmed these findings. Interpretation This large-scale study overcomes the challenges associated with processing and analysis of multiplatform, multicentre DTI data, and effectively demonstrates the anatomical fingerprint patterns of changes in a DTI metric that reflect distinct ALS disease stages. This success paves the way for the use of DTI-based metrics as read-out in natural history, prognostic stratification and multisite disease-modifying studies in ALS.

Amyotrophic Lateral Sclerosis: New Insights into Underlying Molecular Mechanisms and Opportunities for Therapeutic Intervention

Recent years have witnessed a renewed interest in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a late-onset progressive degeneration of motor neurons. The discovery of new genes associated with the familial form of the disease, along with a deeper insight into pathways already described for this disease, has led scientists to reconsider previous postulates. While protein misfolding, mitochondrial dysfunction, oxidative damage, defective axonal transport, and excitotoxicity have not been dismissed, they need to be re-examined as contributors to the onset or progression of ALS in the light of the current knowledge that the mutations of proteins involved in RNA processing, apparently unrelated to the previous old partners, are causative of the same phenotype. Thus, newly envisaged models and tools may offer unforeseen clues on the etiology of this disease and hopefully provide the key to treatment.

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.

Lateral frontal cortex volume reduction in Tourette syndrome revealed by VBM

BackgroundStructural changes have been found predominantly in the frontal cortex and in the striatum in children and adolescents with Gilles de la Tourette syndrome (GTS). The influence of comorbid symptomatology is unclear. Here we sought to address the question of gray matter abnormalities in GTS patients with co-morbid obsessive-compulsive disorder (OCD) and/or attention deficit hyperactivity disorder (ADHD) using voxel-based morphometry (VBM) in twenty-nine adult actually unmedicated GTS patients and twenty-five healthy control subjects.ResultsIn GTS we detected a cluster of decreased gray matter volume in the left inferior frontal gyrus (IFG), but no regions demonstrating volume increases. By comparing subgroups of GTS with comorbid ADHD to the subgroup with comorbid OCD, we found a left-sided amygdalar volume increase.ConclusionsFrom our results it is suggested that the left IFG may constitute a common underlying structural correlate of GTS with co-morbid OCD/ADHD. A volume reduction in this brain region that has been previously identified as a key region in OCD and was associated with the active inhibition of attentional processes may reflect the failure to control behavior. Amygdala volume increase is discussed on the background of a linkage of this structure with ADHD symptomatology. Correlations with clinical data revealed gray matter volume changes in specific brain areas that have been described in these conditions each.

Mind the gap: the mismatch between clinical and imaging metrics in ALS.

Advanced magnetic resonance imaging (MRI) techniques hold the promise to capture upper motor neuron loss and extramotor brain changes in amyotrophic lateral sclerosis (ALS) and as such deliver biomarkers relevant to diagnosis, prognosis and monitoring disease progression. However, a correlation between imaging parameters and clinical metrics has thus far been inconsistent across studies. We discuss the contributing factors to this clinical-imaging correlation gap as well as its implications for future research.

Extent of cortical involvement in amyotrophic lateral sclerosis – an analysis based on cortical thickness

BackgroundBesides the defining involvement of upper and lower motor neurons, the involvement of extramotor structures has been increasingly acknowledged in amyotrophic lateral sclerosis (ALS).MethodsHere we investigated a group of 14 mildly to moderately affected ALS patients and 14 age-matched healthy control participants using cortical thickness analysis. Cortical thickness was determined from high resolution 3D T1 magnetic resonance images and involved semiautomatic segmentation in grey and white matter, cortical alignment and determination of thickness using the Laplace method. In addition to a whole-cortex analysis a region of interest approach was applied.ResultsALS patients showed regions of significant cortical thinning in the pre- and postcentral gyri bilaterally. Further regions of cortical thinning included superior and inferior parietal lobule, angular and supramarginal gyrus, insula, superior frontal, temporal and occipital regions, thus further substantiating extramotor involvement in ALS. A relationship between cortical thickness of the right superior frontal cortex and clinical severity (assessed by the ALS functional rating scale) was also demonstrated.ConclusionsCortical thickness is reduced in ALS not only in motor areas but in widespread non-motor cortical areas. Cortical thickness is related to clinical severity.

The metabolic and endocrine characteristics in spinal and bulbar muscular atrophy

ObjectiveSpinal and bulbar muscular atrophy (SBMA) is caused by an abnormal expansion of the CAG repeat in the androgen receptor gene. This study aimed to systematically phenotype a German SBMA cohort (nxa0=xa080) based on laboratory markers for neuromuscular, metabolic, and endocrine status, and thus provide a basis for the selection of biomarkers for future therapeutic trials.MethodsWe assessed a panel of 28 laboratory parameters. The clinical course and blood biomarkers were correlated with disease duration and CAG repeat length. A subset of 11 patients was evaluated with body fat MRI.ResultsAlmost all patients reported muscle weakness (99%), followed by dysphagia (77%), tremor (76%), and gynecomastia (75%) as major complaints. Creatine kinase was the most consistently elevated (94%) serum marker, which, however, did not relate with either the disease duration or the CAG repeat length. Paresis duration and CAG repeat length correlated with dehydroepiandrosterone sulfate after correction for body mass index and age. The androgen insensitivity index was elevated in nearly half of the participants (48%).ConclusionsMetabolic alterations in glucose homeostasis (diabetes) and fat metabolism (combined hyperlipidemia), and sex hormone abnormalities (androgen insensitivity) could be observed among SBMA patients without association with the neuromuscular phenotype. Dehydroepiandrosterone sulfate was the only biomarker that correlated strongly with both weakness duration and the CAG repeat length after adjusting for age and BMI, indicating its potential as a biomarker for both disease severity and duration and, therefore, its possible use as a reliable outcome measure in future therapeutic studies.

Quantitative Untersuchungen zur Feinmotorik von Parkinson-Patienten mittels MIDI-Technologie

Die Beweglichkeitsstorungen beim idiopathischen Parkinson-Syndrom (IPD) werden eher theoretisch in Hypokinese (Bewegungsverlangsamung), Bradykinese (Amplitudenminderung) und Akinese (Hemmung des Bewegungsstarts) eingeteilt. Diese tragen unter den motorischen Kardinalsymptomen des IPD am deutlichsten zur Gesamtbehinderung der Patienten bei. Ziel dieser Pilotstudie war es, die Moglichkeiten der MIDI-Technologie (Musical Instrument Digital Interface) fur eine genauere Charakterisierung der einzelnen feinmotorischen Komponenten am Beispiel des IPD zu evaluieren. 25 Patienten mit IPD (im medikamentosen ON) sowie 31 gesunde Kontrollen, die nie zuvor ein Musikinstrument gespielt hatten, wurden an einem elektronischen Klavier (Yamaha CLP 110) untersucht. Dabei wurden funf unterschiedliche Ubungen fur jeweils 15 Sekunden zweimalig bei definierter Lautstarke mit hochstmoglicher Geschwindigkeit ausgefuhrt: Einzeltapping mit dem Zeigefinger (2. F.), Triller (zwischen 2. u. 3. F.), Sequenz (1–2–3–4–5–4–3–2–1–2–3-usw.), Fingersprunge (mit dem Zeigefinger im Wechsel uber 2 Oktaven). Berechnet wurden die Frequenz (F), Anschlagsgeschwindigkeit (V), Anschlagsdauer (DUR), das Intervall zwischen zwei Tastenanschlagen (IOI) sowie das Intervall vom Ende des einen bis zum Beginn des folgenden Anschlags (ISI) fur jede Taste getrennt. Die Auswertung der Variablen erfolgte mit SPSS 13.0. Die Anschlagsfrequenz wie -dauer waren bei allen Aufgaben bis auf die Sequenz, welche die hochsten koordinativen Aufgaben an die Probanden stellte, bei den IPD Patienten gegenuber Kontrollen vermindert. Die Anschlagsgeschwindigkeit zeigte sich signifikant beim Einzeltapping und den Fingersprungen reduziert. Die einzigen Variablen, die sich bei allen Aufgaben zwischen Patienten und Kontrollen unterschieden, waren IOI und ISI. Mit einem einfachen Fingertapping konnte bereits gezeigt werden, dass sich die MIDI- Technologie zur objektiven Quantifizierung der Bewegungseinschrankung bei IPD Patienten eignet. Die Ergebnisse der vorliegen Pilotstudie deuten an, dass auch unterschiedliche Komponenten der Feinmotorik untersucht werden konnen, die fur die Charakterisierung auch anderer Bewegungsstorungen genutzt werden konnten. Hierbei konnte die Frequenz ein Mas fur die Hypokinese darstellen, die Anschlagsgeschwindigkeit als Parameter fur die Bradykinese und das Intervall zwischen den Tastenanschlagen als Parameter fur die Akinese genutzt werden.

Kortikale Atrophie bei Amyotropher Lateralsklerose in der multizentrischen Kernspinmorphometrie

Die Amyotrophe Lateralsklerose (ALS) ist eine rasch progrediente neurodegenerative Systemerkrankung mit dominanter Beteiligung des motorischen Systems. Morphometrische MRT-Studien haben in der Vergangenheit unterschiedliche Resultate bezuglich des Ausmases der kortikalen Beteiligung ergeben, die u.a. auf technische Unterschiede oder kleine Patientenkollektive zuruckzufuhren sind. Ziel der vorliegen Studie war es, die multizentrische Anwendbarkeit der voxelbasierten Morphometrie (VBM) bei einem neuropathologisch ausreichend gut charakterisierten Krankheitsbild wie der ALS zu uberprufen. Es wurde von insgesamt 60 ALS Patienten auf unterschiedlichen 1,5 Tesla Scannern ein volumetrischer T1-Datensatz erhoben (Hannover n=21/GE, Ulm n=22/Siemens, Magdeburg n=17/GE). Pro Zentrum wurde eine gleiche Anzahl altersentsprechender Kontrollen (gesamt n=60) gemessen. Die Bilder wurden nach dem optimierten VBM Protokoll mit SPM2 analysiert. Fur die Template-Erstellung wurden die Kontrollen aller Zentren verwendet. Nur die modulierten Daten der grauen Substanz gingen in die weitere Auswertung ein. Gruppenvergleiche wurden basierend auf dem allgemeinen linearen Modell mittels ANOVA und dem Zentrum als nuisance Variable durchgefuhrt. Die globale Normalisierung erfolgte mittels proportional scaling. Fur die Vergleiche von Patienten und Kontrollen innerhalb der verschiedenen Zentren fanden sich unterschiedliche Ergebnisse bezuglich der Beteiligung des primar motorischen Kortex und frontaler Areale (p<0,001, unkorrigiert). Die Gesamtanalyse ergab eine ausgepragte regionale Atrophie der grauen Substanz des prazentralen Gyrus sowie pramotorischer Gebiete (p<0,05, korrigiert). Regionale Atrophien in frontalen Bereichen liesen sich hier nicht nachweisen. Wie in dieser bisher grosten VBM Studie bei ALS Patienten gezeigt werden konnte, ist die regionale Atrophie des primar motorischen Kortex charakteristisch fur die ALS. Die Ergebnisse zeigen einen validen Informationsgewinn durch die multizentrische Studie, der sich mit Befunden von post-mortem Analysen bei der Erkrankung deckt. Hierdurch ergeben sich neue Perspektiven fur eine zentrenubergreifende Anwendbarkeit der voxelbasierten Morphometrie.