Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3,033 (1,482 BD and 1,551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega-and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum ( R 2 = 0.041, P corr < 0.001) and cingulum (right: R 2 = 0.041, left: R 2 = 0.040, P corr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD.

Background and Objectives To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti–interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein–IgG–associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). Methods Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab. Results Patients received TCZ for 23.8 months (median; interquartile range 13.0–51.1 months), with an IV dose of 8.0 mg/kg (median; range 6–12 mg/kg) every 31.6 days (mean; range 26–44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5–5) to 0 (range 0–0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0–5] to 0 [range 0–4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0–3.0] to 0.2 [range 0–2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy. Discussion This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

We thank Dr. Chen for his comment. We included neuromyelitis optica spectrum disorder (NMOSD) patients with longitudinal visual-evoked potential (VEP) data covering ≥3 months. We calculated the changes per year using regression analysis. For eyes with <12 months longitudinal OCT follow-up available, the change rate was interpolated. However, as interpolation of data with short intervals can lead to amplification of measurement variability, we also performed a more conservative subanalysis including only eyes with ≥12 months interval between VEP measurements. For this subanalysis, only 58% and 69% of eyes were available for the investigation of the rates of change of latencies and amplitudes, respectively. Of note, it has previously been reported that the amplitudes show a stronger variability of measurement compared to latencies.1,2 Therefore, we believe that the sample size was not sufficient to achieve statistical significance in the subanalysis. Moreover, the prominent outliers of amplitude changes of eyes with <12 months of follow-up are likely to result from amplification of measurement variability and should be interpreted with caution. On the other hand, the latency findings show consistent and reliable increases also in the conservative ≥12 months subanalysis, thus representing the main finding of our study and a better parameter to investigate chronic changes.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum ( R 2 = 0.041, P corr < 0.001) and cingulum (right: R 2 = 0.041, left: R 2 = 0.040, P corr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Background: Today, no specific test for the diagnosis of multiple sclerosis (MS) is available due to the lack of characteristic symptoms at beginning. This circumstance also complicates estimation of disease progression. Recent findings provided evidence for early, non-lesional cerebellar damage in patients with (clinically definite) relapsing-remitting MS. Objective: To investigate if microstructural cerebellar alterations can also serve as early structural biomarker for disease progression and conversion from clinically isolated syndrome (CIS) to MS. Methods: 46 patients diagnosed with CIS and 26 age-matched healthy controls were admitted to high-resolution MRI including diffusion tensor imaging (DTI) to examine atrophy and microstructural integrity of the cerebellum. Microstructural integrity of cerebellar white matter was assessed by fractional anisotropy (FA) as derived from DTI. Results: Although all 46 patients of our CIS cohort showed no cerebellar lesions in structural MRI (T1w, T2w, FLAIR), their mean cerebellar FA was already reduced compared to healthy controls. Significant FA reduction at follow-up DTI 6 months after baseline examination was observed. In 16 patients that converted to MS, we found a correlation between initial cerebellar FA and conversion latency (R = 0.71, p < 0.002). Initial cerebellar FA under FAcrit = 0.352 predicted conversion into relapsing-remitting MS within 24 months (FAcrit: mean cerebellar FA of patients with early MS, determined in another study). Conclusion: DTI seems to reflect early tissue injury in beginning MS, when atrophy and lesions are not yet detectable. Decreased cerebellar FA in patients with CIS might indicate an active and unstable disease stage, resulting in a shorter conversion time into MS.

ObjectiveThe absence of neurobiological diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We investigated if changes in fractional anisotropy (FA) could help to differentiate BD from UD in the state of depression.MethodsUsing diffusion tensor imaging (DTI) we employed a voxel‐based analysis approach to examine fractional anisotropy (FA) in 86 patients experiencing an acute major depressive episode according to DSM‐IV (N=39 BD, mean age 39.2 years; N=43 UD, mean age 39.0 years), and 42 healthy controls (HC, mean age 36.1 years). The groups did not differ in sex, age or total education time. FA was investigated in white matter (FA >.2) and hypothesis‐driven anatomically defined tracts (region‐of‐interest [ROI] analysis). Additionally, an exploratory gray matter FA analysis was performed.ResultsWhite matter analysis showed decreased FA in the right corticospinal tract in UD vs HC and in the right corticospinal tract/superior longitudinal fascicle in BD vs HC and also in BD vs UD. ROI analysis revealed decreased FA in BD vs UD in the corpus callosum and in the cingulum. Gray matter exploratory analysis revealed decreased FA in the left middle frontal gyrus and in the right inferior frontal gyrus in UD vs HC, and in the left superior medial gyrus in BD vs HC.ConclusionThis is one of very few studies directly showing differences in FA between BD and UD. Gray matter FA changes in prefrontal areas might be precursors for future prefrontal gray matter abnormalities in these disorders.

Objective: To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration. Methods: Three patients with subacute to chronic cerebellar ataxia and controls underwent detailed clinical and neuropsychological assessment together with quantitative high-resolution structural MRI. Sera and CSF were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IFA) and immunoblot. Immunoprecipitation with lysates of hippocampus and cerebellum combined with mass spectrometric analysis was used to identify the autoantigen, which was verified by recombinant expression in HEK293 cells and use in several immunoassays. Multiparameter flow cytometry was performed on peripheral blood and CSF, and peripheral blood was subjected to T-cell receptor spectratyping. Results: Patients presented with a subacute to chronic cerebellar and brainstem syndrome. MRI was consistent with cortical and cerebellar gray matter atrophy associated with subsequent neuroaxonal degeneration. IFA screening revealed strong immunoglobulin G1 reactivity in sera and CSF with hippocampal and cerebellar molecular and granular layers, but not with a panel of 30 recombinantly expressed established neural autoantigens. Neurochondrin was subsequently identified as the target antigen, verified by IFA and immunoblot with HEK293 cells expressing human neurochondrin as well as the ability of recombinant neurochondrin to neutralize the autoantibodies' tissue reaction. Immune phenotyping revealed intrathecal accumulation and activation of B and T cells during the acute but not chronic phase of the disease. T-cell receptor spectratyping suggested an antigen-specific T-cell response accompanying the formation of antineurochondrin autoantibodies. No such neurochondrin reactivity was found in control cohorts of various neural autoantibody-associated neurologic syndromes, relapsing-remitting multiple sclerosis, cerebellar type of multiple system atrophy, hereditary cerebellar ataxias, other neurologic disorders, or healthy donors. Conclusion: Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration.

Objective: To define an ALS-specific region of interest (ROI) for motor tracts in Amyotrophic lateral Sclerosis (ALS) to detect white matter changes and predict progression types of ALS. Background: Serial follow-up MRI’s were obtained for safety and monitoring ALS progression during longterm G-CSF (Filgrastim) treatment on a named patient basis. Quantitative analysis of white matter fractional anisotropy (FA) may represent a sensitive structural biomarker correlating to clinical courses of ALS patients. Design/Methods: ALS patients were treated with G-CSF in addition to standard therapy. Application modes and doses were individually adapted, treatment duration up to 5 years. Clinical exams and ALS-FRS-R were conducted monthly, MRI obtained every three months. Statistical comparison of 12 ALS patients and healthy controls revealed significant differences in FA in a specific part of motor tracts, defined as a new ALS-specific ROI. We evaluated longterm MRI datasets of 12 ALS patients and 4 controls. Statistical analysis (two-sided T-tests, a 2×2 univariate ANOVA) focused on baseline FA and decline in FA over segments of three months, including co-factors gender and progression type , and the covariate age . Results: The mean ALS-FRS-R at start of treatment was 40.08 (± 1.25). Mean ALS-FRS-R decline per year served as a cut off value separating fast and slow progressing ALS patients. Baseline FA of the ALS-specific ROI was significantly lower for ALS patients than for healthy controls. Decline in FA in the ALS-specific ROI was significantly higher in fast progressing, especially female, ALS patients. Conclusions: Diffusion-weighted FA may be considered as a MRI marker for the description of ALS-specific white matter pathology. The approach towards an ALS-specific structural marker for white matter degeneration linked to ALS-FRS-R decline may add in predicting disease progression. Study Supported by: The current study is funded by the German Federal Ministry of Education and Research (BMBF, Project GO-Bio). Disclosure: Dr. Wirth has nothing to disclose. Dr. Khomenko has nothing to disclose. Dr. Baldaranov has nothing to disclose. Dr. Johannesen has nothing to disclose. Dr. Kobor has nothing to disclose. Dr. Brunn has received personal compensation for activities with NeuroVision Pharma GmbH, Germany. Dr. Greenlee has nothing to disclose. Dr. Deppe has nothing to disclose. Dr. Bogdahn has nothing to disclose.

OBJECTIVE Aim of our study was to detect individual disease progression patterns of ALS patients and visualize them as function of extrinsic cortical curvature.BACKGROUND G-CSF may modulate clinical progression of patients with motor neuron disease. Serial follow-up MRI`s ware obtained for safety and monitoring disease progression during longterm compassionate use of G-CSF in ALS patients. Quantitative analysis of gray matter (GM) and white matter (WM) including cortical extrinsic curvature seems to represent a robust and sensitive biomarker for detecting changes of structure and GM/WM-proportion.METHODS So far, we evaluated MRI datasets of 4 out of 23 ALS patients. The mean ALS Functional Rating Scale revised (ALS-FRS-R) at start of treatment was 36.75. Patients were treated with individually adapted s.c. G-CSF with range of 150-720 MioIU/month up to 5 years, inclusive standard treatment. Monthly control visits with clinical exams and ALS-FRS-R were performed. Cranial MRI (3D high- resolution structural and diffusion weighted MRI at 1,5T) was obtained every three months. Extended and fully automated data post-processing was retrospectively analyzed in a pipeline as described by Deppe et.al. 2014. Briefly, DTI image-processing steps resulted in fractional anisotropy (FA) maps to detect microstructural alterations of WM. Surface reconstruction was applied to all structural data sets for individual quantitative analysis of GM, WM and extrinsic cortical curvature.RESULTS For each patient under longterm G-CSF treatment an individual disease pattern could be visualized. FA decline over time significantly correlated with disease course. Increase of extrinsic cortical curvature, FA decline of pyramidal tract, changes in GM and WM showed very individual patterns.CONCLUSIONS Earlier detection of individual quantitative parameters could enable to anticipate the potential future course of disease progression. Cortical curvature measurement may be considered as an additional marker for the evaluation of new ALS therapies. Disclosure: Dr. Baldaranov has nothing to disclose. Dr. Khomenko has nothing to disclose. Dr. Kobor has nothing to disclose. Dr. Johannesen has nothing to disclose. Dr. Grimm has nothing to disclose. Dr. Wirth has nothing to disclose. Dr. Bruun has nothing to disclose. Dr. Grassinger has nothing to disclose. Dr. Schuirer has nothing to disclose. Dr. Schulte-Mattler has nothing to disclose. Dr. Deppe has nothing to disclose. Dr. Bogdahn has nothing to disclose.

Objectives: Treatment development in ALS needs validated biomarkers. We initiated long-term follow up including assessment of multiple potential biomarkers in ALS patients treated with G-CSF. Here we present a retrospective analysis as a basis for further initiatives. Background: Not only pathogenic heterogeneity but also individual diversity in clinical courses are hallmarks for ALS. Measurement of pyramidal tract integrity by FA (Fractional Anisotropy, MRI) and estimation of active motor units by neurophysiology (MUNIX, e.g. hypothenar muscle) as markers of disease course and potential therapy effects are surrogate biomarkers. FA and MUNIX have already demonstrated sensitivity to disease progression in ALS patients. Inflammatory cells and cytokines are relevant co-factors of individual disease progression. Methods: Clinical ALS score (ALS-FRS-r), hematology and clinical chemistry were obtained monthly in 23 ALS patients (15 male, 8 female, mean age 51, 4 yrs.), who received G-CSF treatments up to 5 years. As further biomarkers (1) upper motor neuron integrity (DWI-MRI, FA) and (2) lower motor neuron function (MUNIX) were assessed every 3 months, as well as further cellular and inflammatory markers. Results: Disease progression (ALSFRS-r-decline) correlated significantly (p<0.0001) with loss of lower motor neurons (MUNIX-decline), and on an individual patient level, with decline in upper motor neuron integrity (FA-decline). Patients with more pronounced clinical progression (lower ALS-FRS-r) mobilized less monocytes (p=0.048) and pluripotent hematological stem cells (CD34+38-) (p=0.037) but more eosinophils (p=0.002) into peripheral blood. Time sectional separation of biomarkers may indicate individual response patterns. Conclusions: Quantitative markers for upper and lower motor neuron integrity such as FA and MUNIX as well as inflammatory cells such as monocytes, eosinophils or stem cells are promising biomarkers for ALS treatment development. Data are extremely robust: Funding for a prospective clinical trial is urgently needed. Acknowledgements: BMBF GO-Bio, BMBF MND Network Germany, PROACT-Database USA

Background: There is an unmet need for screening methods to detect and quantify cerebral small vessel disease (SVD). Transcranial Doppler ultrasound (TCD) flow spectra of the larger intracranial arteries probably contain relevant information about the microcirculation. However, it has not yet been possible to exploit this information as a valuable biomarker. Methods: We developed a technique to generate normalized and averaged flow spectra during middle cerebral artery Doppler ultrasound examinations. Second, acceleration curves were calculated, and the absolute amount of the maximum positive and negative acceleration was calculated. Findings were termed ‘TCD-profiling coefficient' (TPC). Validation study: we applied this noninvasive method to 5 young adults for reproducibility. Degenerative microangiopathy study: we also tested this new technique in 30 elderly subjects: 15 free of symptoms but with MRI-verified presence of cerebral SVD, and 15 healthy controls. SVD severity was graded according to a predefined score. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) study: TPC values of 10 CADASIL patients were compared with those of 10 healthy controls. Pulse wave analysis and local measurements of carotid stiffness were also performed. CADASIL patients were tested for cognitive impairment with the Montreal Cognitive Assessment scale. White matter and basal ganglia lesions in their cerebral MRI were evaluated according to the Wahlund score. Results: Validation study: the technique delivered reproducible results. Degenerative microangiopathy study: patients with SVD had significantly larger TPCs compared with controls (SVD: 2,132; IQR 1,960-2,343 %/s vs. controls: 1,935; IQR 1,782-2,050 %/s, p = 0.01). TPC values of subjects with SVD significantly correlated with SVD severity scores (R = 0.58, n = 15, p < 0.05). CADASIL study: TPC values of CADASIL patients were significantly higher than values of the controls (CADASIL: 2,504; IQR 2,308-2,930 %/s vs. controls 2,084; 1,839-2,241 %/s, p = 0.008), and also significantly higher than the TPC values of the patients with SVD from the degenerative microangiopathy study (p = 0.007). CADASIL patients had significantly worse cognitive test results than healthy controls. Conclusion: TCD-profiling detects impairment of the cerebral microcirculatory state. The suitability of the TCD-profiling for the evaluation of cerebral microangiopathy was confirmed.

Recent studies on patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS) demonstrated thalamic atrophy. Here we addressed the following question: Is early thalamic atrophy in patients with CIS and relapsing-remitting MS (RRMS) mainly a direct consequence of white matter (WM) lesionsas frequently claimedor is the atrophy stronger correlated to silent (nonlesional) microstructural thalamic alterations? One-hundred and ten patients with RRMS, 12 with CIS, and 30 healthy controls were admitted to 3T magnetic resonance imaging. Fractional anisotropy (FA) was computed from diffusion tensor imaging (DTI) to assess thalamic and WM microstructure. The relative thalamic volume (RTV) and thalamic FA were significantly reduced in patients with CIS and RRMS relative to healthy controls. Both measures were also correlated. The age, gender, WM lesion load, thalamic FA, and gray matter volume-corrected RTV were reduced even in the absence of thalamic and extensive white matter lesionsalso in patients with short disease duration (24 months). A voxel-based correlation analysis revealed that the RTV reduction had a significant effect on local WM FAin areas next to the thalamus and basal ganglia. These WM alterations could not be explained by WM lesions, which had a differing spatial distribution. Early thalamic atrophy is mainly driven by silent microstructural thalamic alterations. Lesions do not disclose the early damage of thalamocortical circuits, which seem to be much more affected in CIS and RRMS than expected. Thalamocortical damage can be detected by DTI in normal appearing brain tissue. Hum Brain Mapp 37:1866-1879, 2016. (c) 2016 Wiley Periodicals, Inc.

Objectives: Long-term compassionate use of granulocyte-colony-stimulating factor (G-CSF, filgrastim) in ALS patients. Background: G-CSF is a long-term established and safe hematopoietic growth factor that may potentially compensate rapid neuronal loss in ALS patients by neuroprotection, neurogenesis and immunomodulation. Although animal models seemed promising, pilot clinical trials were inconclusive. Relevant clinical improvement might have been missed due to inadequate dosing, and far too short duration of treatment and follow up. Bone marrow stem cells are directly involved in G-CSF treatment; their differentiation markers may serve as additional biomarkers and help understand the mode of action. Methods: 23 ALS patients (15m, 8f, mean ALS-FRS-r at start 36.75) were treated with G-CSF plus standard therapy after informed consent in an outpatient regimen. Application modes were individually adapted (150-720 MioIU/month s.c.). Monthly visits with ALSFRS-r, clinical chemistry, blood smears and bone marrow mobilization parameters were performed, followed by cerebral MRI and neurophysiological measurements on a 3-monthly basis throughout the long-term intervention up to 5 yrs. Results: Safety and compliance were excellent; we found no unexpected changes in blood smears. G-CSF was well tolerated, although acceptable mild or moderate bone pain was frequently reported. G-CSF resulted in effective hematopoietic stem cell mobilization (increase in CD34+ and CD34+38- cells). We found bone marrow colony forming capacity with G-CSF treatment to be associated to overall survival (OS). In retrospective analysis a significantly lower ALS progression rate (p<0.0001) and a clinically relevant prolongation of OS (p<0.0001) were observed in long-term G-CSF treated ALS patients compared to the current PRO-ACT database. Without respect to dosage, median OS since G-CSF treatment initiation was 28,5 months. Conclusions: Long-term administration of G-CSF in ALS patients is safe, well tolerated and feasible. Data are very robust; a prospective clinical trial is urgently needed. Acknowledgements: BMBF GO-BIO, BMBF MND Network Germany, PROACT-Database USA

Putamen atrophy and its long-term progress during disease course were recently shown in patients with multiple sclerosis (MS). Here we investigated retrospectively the time point of atrophy onset in patients with relapsing-remitting MS (RRMS). 68 patients with RRMS and 26 healthy controls (HC) were admitted to 3T MRI in a cross-sectional study. We quantitatively analyzed the putamen volume of individual patients in relation to disease duration by correcting for age and intracranial volume (ICV). Patient's relative putamen volume (RPV), expressed in percent of ICV, was significantly reduced compared to HC. Based on the correlation between RPV and age, we computed the age-corrected RPV deviation (ΔRPV) from HC. Patients showed significantly negative ΔRPV. Interestingly, the age-corrected ΔRPV depended logarithmically on disease duration: Directly after first symptom manifestation, patients already showed a reduced RPV followed by a further degressive volumetric decline. This means that atrophy progression was stronger in the first than in later years of disease. Putamen atrophy starts directly after initial symptom manifestation or even years before, and progresses in a degressive manner. Due to its important role in neurological functions, early detection of putamen atrophy seems necessary. High-resolution structural MRI allows monitoring of disease course.

BACKGROUND:Deterioration of fine motor control of the tongue is common in Multiple Sclerosis (MS) and has a major impact on quality of life. However, the underlying neuronal substrate is largely unknown. Here, we aimed to explore the association of tongue motor dysfunction in MS patients with overall clinical disability and structural brain damage.METHODS:We employed a force transducer based quantitative-motor system (Q-Motor) to objectively assess tongue function in 33 patients with MS. The variability of tongue force output (TFV) and the mean applied tongue force (TF) were measured during an isometric tongue protrusion task. Twenty-three age and gender matched healthy volunteers served as controls. Correlation analyses of motor performance in MS patients with individual disease burden as expressed by the Expanded Disability Status Scale (EDSS) and with microstructural brain damage as measured by the fractional anisotropy (FA) on Diffusion Tensor Imaging were performed.RESULTS:MS patients showed significantly increased TFV and decreased TF compared to controls (p < 0.02). TFV but not TF was correlated with the EDSS (p < 0.04). TFV was inversely correlated with FA in the bilateral posterior limb of the internal capsule expanding to the brain stem (p < 0.001), a region critical to tongue function. TF showed a weaker, positive and unilateral correlation with FA in the same region (p < 0.001).CONCLUSIONS:Changes in TFV were more robust and correlated better with disease phenotype and FA changes than TF. TFV might serve as an objective and non-invasive outcome measure to augment the quantitative assessment of motor dysfunction in MS.

Introduction: The underlying pathophysiology of neurological complications in patients with hemolytic-uremic syndrome (HUS) remains unclear. It was recently attributed to a direct cytotoxic effect of Shiga toxin 2 (Stx2) in the thalamus. Conventional MRI of patients with Stx2-caused HUS revealed - despite severe neurological symptoms - only mild alterations if any, mostly in the thalamus. Against this background, we questioned: Does diffusion tensor imaging (DTI) capture the thalamic damage better than conventional MRI? Are neurological symptoms and disease course better reflected by thalamic alterations as detected by DTI? Are other brain regions also affected?Methods: Three women with serious neurological deficits due to Sbc2-associated HUS were admitted to MRI/DTI at disease onset. Two of them were longitudinally examined. Fractional anisotropy (FA) and mean diffusivity were computed to assess Stx2-caused microstructural damage.Results: Compared to 90 healthy women, all three patients had significantly reduced thalamic FA. Thalamic mean diffusivity was only reduced in two patients. DTI of the longitudinally examined women demonstrated slow normalization of thalamic FA, which was paralleled by clinical improvement.Conclusion: Whereas conventional MRI only shows slight alterations based on subjective evaluation, DTI permits quantitative, objective, and longitudinal assessment of cytotoxic cerebral damage in individual patients. (C) 2015 Elsevier B.V. All rights reserved.