Viktor Hartung

Longitudinal diffusion tensor imaging in amyotrophic lateral sclerosis

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, caused by progressive loss of motor neurons. Changes are widespread in the subcortical white matter in ALS. Diffusion tensor imaging (DTI) detects pathological changes in white matter fibres in vivo, based on alterations in the degree (diffusivity, ADC) and directedness (fractional anisotropy, FA) of proton movement.Methods24 patients with ALS and 24 age-matched controls received 1.5T DTI. FA and ADC were analyzed using statistical parametric mapping. In 15 of the 24 ALS patients, a second DTI was obtained after 6 months.ResultsDecreased FA in the corticospinal tract (CST) and frontal areas confirm existing results. With a direct comparison of baseline and follow-up dataset, the progression of upper motor neuron degeneration, reflected in FA decrease, could be captured along the CST and in frontal areas. The involvement of cerebellum in the pathology of ALS, as suspected from functional MRI studies, could be confirmed by a reduced FA (culmen, declive). These structural changes correlated well with disease duration, ALSFRS-R, and physical and executive functions.ConclusionDTI detects changes that are regarded as prominent features of ALS and thus, shows promise in its function as a biomarker. Using the technique herein, we could demonstrate DTI changes at follow-up which correlated well with clinical progression.

Diffusion tensor imaging patterns differ in bulbar and limb onset amyotrophic lateral sclerosis

BACKGROUND Amyotrophic lateral sclerosis (ALS) is characterized by pronounced clinical heterogeneity in terms of onset and disease progression. Widespread changes in white matter fibres could be observed by diffusion tensor imaging (DTI), which detects alterations in the degree (diffusivity, ADC) and directedness (fractional anisotropy, FA) of proton movement. The aim of the current study was to determine whether different ALS onset types were reflected in different DTI brain patterns. METHODS Seventeen patients with a diagnosis of ALS (6 bulbar, 11 limb onset) and seventeen age-matched controls received 1.5T DTI, where FA and ADC were analyzed using statistical parametric mapping. RESULTS In ALS patients, an increased diffusivity in the white matter was found below the precentral gyrus and along the corticospinal tract (CST) right into the internal capsule. The FA was decreased in the posterior limb of internal capsule and in the subcortical white matter in the precentral gyrus. In bulbar onset increased diffusivity was found in the CST, whilst in limb onset, frontal subcortical areas displayed an increased diffusivity. CONCLUSION DTI changes can be regarded as prominent features in ALS. Herein we were able to demonstrate discriminating brain DTI patterns due to bulbar or limb onset.

Voxel-Based MRI Intensitometry Reveals Extent of Cerebral White Matter Pathology in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons. Advanced MRI techniques such as diffusion tensor imaging have shown great potential in capturing a common white matter pathology. However the sensitivity is variable and diffusion tensor imaging is not yet applicable to the routine clinical environment. Voxel-based morphometry (VBM) has revealed grey matter changes in ALS, but the bias-reducing algorithms inherent to traditional VBM are not optimized for the assessment of the white matter changes. We have developed a novel approach to white matter analysis, namely voxel-based intensitometry (VBI). High resolution T1-weighted MRI was acquired at 1.5 Tesla in 30 ALS patients and 37 age-matched healthy controls. VBI analysis at the group level revealed widespread white matter intensity increases in the corticospinal tracts, corpus callosum, sub-central, frontal and occipital white matter tracts and cerebellum. VBI results correlated with disease severity (ALSFRS-R) and patterns of cerebral involvement differed between bulbar- and limb-onset. VBI would be easily translatable to the routine clinical environment, and once optimized for individual analysis offers significant biomarker potential in ALS.

Susceptibility-Weighted Imaging Provides Insight into White Matter Damage in Amyotrophic Lateral Sclerosis

Background Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disorder, characterised by widespread white matter damage. There is growing evidence that disturbances in iron metabolism contribute to white matter alterations. Materials & Methods We analysed the data of susceptibility-weighted imaging (SWI) of white matter in a cohort of 27 patients with ALS and 30 healthy age-matched controls. Results Signal alterations were found on SWI in the corpus callosum; along the corticospinal tract (subcortical motor cortex, posterior limb of the internal capsule and brainstem levels) and in the subgyral regions of frontal, parietal, temporal, occipital and limbic lobes. Alterations of white matter in the corpus callosum correlated with disease severity as assessed by the revised ALS functional rating scale. Conclusion SWI is capable of indicating iron and myelin disturbances in white matter of ALS patients. The SWI patterns observed in this study suggest that widespread alterations due to iron disturbances occur in patients with ALS and correlate with disease severity.

P48. Progression of cerebellar involvement in amyotrophic lateral sclerosis as seen by SUIT/ CAT12 voxel-based morphometry and D50 disease modelling

Background The cerebellum is essential for intact motor function and has an important role in cognitive and neuropsychiatric processes. It is known that the cerebellum is involved in ALS pathology, but the role of gray matter (GM) and white matter (WM) changes is still unclear. Objective The current study sets out to describe the involvement of the cerebellum with regard to the site of onset, disease phases, degree of disability and disease progression rate in a large cohort of well characterized ALS patients. Methods T1-weighted MRI of 84 ALS patients and 63 healthy controls were analyzed. Based on these clinical parameters, patients were classified into the subgroups and analyzed to determine changes in the GM and WM. D50 is a new parameter to describe the ALS disease course (D50 = time point when ALSFRS-R drops to 24). Based on D50, ALS disease course can be divided in different disease phases (I-IV), each phase covering half of D50. ALSFRS-R, Δ ALSFRS-R, and D50 were correlated to MRI data of all ALS-patients and patients in phase I and II to show the differences in volume changing patterns. Results The mean age of the patients was 60 ± 11.49y, m: f was 49:35, ALSFRS-R at MRI was 37 ± 7.29, mean Δ ALSFRS-R was 0.68 ± 0.54, average disease duration was 23 ± 30.08 months, D50 was 38.63 ± 32,87 months. The patient group included 24 bulbar and 60 limb onsets. 46 patients had a low degree of disability (ALSFRS-R ⩾ 38), 38 were highly impaired (ALSFRS-R  Δ ALSFRS-R, we subgrouped patients in rapid ( Δ ALSFRS-R > 1.5; n  = 9) and slow ( Δ ALSFRS-R  n  = 36). Additionally, the rapid (D50  n  = 9) and slow (D50 > 40mo; n  = 25) subgroups were categorized based on D50. Late phase and high degree of disability were characterized by pronounced GM reduction in cerebellar regions, whereas WM alterations were localized primarily in brainstem. Rapid progressors show more GM atrophy. Conclusion Using a spatially unbiased atlas template of the cerebellum and brainstem (SUIT) toolbox and a Computational Anatomy Toolbox for SPM (CAT12) in a large cohort of ALS patients, we were able to indicate that the subtypes demonstrate different patterns of GM-atrophy in cerebellum. These results might be important to understand the pathophysiology of ALS. D50 seems to be more sensitive then Δ ALSFRS-R and could be used as a progression biomarker in combination with Voxel-based Morphometry (VBM). Acknowledgment This research is supported by BMBF (Bundesministerium fur Bildung and Forschung) in the framework of the E-RARE programme (PYRAMID), JPND (OnWebDUALS) of the European Union and the Dt. Gesellschaft fur Muskelkranke (DGM).