Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders.

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.

Extremely low-energy ARPES of quantum well states in cubic-GaN/AlN and GaAs/AlGaAs heterostructures.

Quantum well (QW) heterostructures have been extensively used for the realization of a wide range of optical and electronic devices. Exploiting their potential for further improvement and development requires a fundamental understanding of their electronic structure. So far, the most commonly used experimental techniques for this purpose have been all-optical spectroscopy methods that, however, are generally averaging in momentum space. Additional information can be gained by angle-resolved photoelectron spectroscopy (ARPES), which measures the electronic structure with momentum resolution. Here we report on the use of extremely low-energy ARPES (photon energy ~ 7 eV) to increase depth sensitivity and access buried QW states, located at 3 nm and 6 nm below the surface of cubic-GaN/AlN and GaAs/AlGaAs heterostructures, respectively. We find that the QW states in cubic-GaN/AlN can indeed be observed, but not their energy dispersion, because of the high surface roughness. The GaAs/AlGaAs QW states, on the other hand, are buried too deep to be detected by extremely low-energy ARPES. Since the sample surface is much flatter, the ARPES spectra of the GaAs/AlGaAs show distinct features in momentum space, which can be reconducted to the band structure of the topmost surface layer of the QW structure. Our results provide important information about the samples' properties required to perform extremely low-energy ARPES experiments on electronic states buried in semiconductor heterostructures.

Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders.

OBJECTIVE: To investigate if patients with neuromyelitis optica spectrum disorder (NMOSD) develop subclinical visual pathway impairment independent of acute attacks. METHODS: A total of 548 longitudinally assessed full-field visual evoked potentials (VEP) of 167 patients with NMOSD from 16 centers were retrospectively evaluated for changes of P100 latencies and P100-N140 amplitudes. Rates of change in latencies (RCL) and amplitudes (RCA) over time were analyzed for each individual eye using linear regression and compared using generalized estimating equation models. RESULTS: The rates of change in the absence of optic neuritis (ON) for minimal VEP intervals of ≥3 months between baseline and last follow-up were +1.951 ms/y (n = 101 eyes; SD = 6.274; p = 0.012) for the P100 latencies and -2.149 µV/y (n = 64 eyes; SD = 5.013; p = 0.005) for the P100-N140 amplitudes. For minimal VEP intervals of ≥12 months, the RCL was +1.768 ms/y (n = 59 eyes; SD = 4.558; p = 0.024) and the RCA was -0.527 µV/y (n = 44 eyes; SD = 2.123; p = 0.111). The history of a previous ON >6 months before baseline VEP had no influence on RCL and RCA. ONs during the observational period led to mean RCL and RCA of +11.689 ms/y (n = 16 eyes; SD = 17.593; p = 0.003) and -1.238 µV/y (n = 11 eyes; SD = 3.708; p = 0.308), respectively. CONCLUSION: This first longitudinal VEP study of patients with NMOSD provides evidence of progressive VEP latency delay occurring independently of acute ON. Prospective longitudinal studies are needed to corroborate these findings and help to interpret the clinical relevance.

Correction: Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals.

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 (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 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.

Non-lesional cerebellar damage in patients with clinically isolated syndrome: DTI measures predict early conversion into clinically definite multiple sclerosis.

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.

A voxel-based diffusion tensor imaging study in unipolar and bipolar depression.

OBJECTIVE: The 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. METHODS: Using 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. RESULTS: White 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. CONCLUSION: This 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.

Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration.

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.

Early silent microstructural degeneration and atrophy of the thalamocortical network in multiple sclerosis.

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) lesions-as frequently claimed-or 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 3 T 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 lesions-also 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 FA-in 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. © 2016 Wiley Periodicals, Inc.

TCD-Profiling Using AVERAGE. A New Technique to Evaluate Transcranial Doppler Ultrasound Flow Spectra of Subjects with Cerebral Small Vessel Disease.

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.

Evidence for early, non-lesional cerebellar damage in patients with multiple sclerosis: DTI measures correlate with disability, atrophy, and disease duration.

BACKGROUND: Common symptoms of multiple sclerosis (MS) such as gait ataxia, poor coordination of the hands, and intention tremor are usually the result of dysfunctionality in the cerebellum. Magnetic resonance imaging (MRI) has frequently failed to detect cerebellar damage in the form of inflammatory lesions in patients presenting with symptoms of cerebellar dysfunction. OBJECTIVE: To detect microstructural cerebellar tissue alterations in early MS patients with a "normal appearing" cerebellum using diffusion tensor imaging (DTI). METHODS: A total of 68 patients with relapsing-remitting MS (RRMS) and without cerebellar lesions and 26 age-matched healthy controls were admitted to high-resolution MRI and DTI to assess microstructure and volume of the cerebellar white matter (CBWM). RESULTS: We found cerebellar fractional anisotropy (FA) and CBWM volume reductions in the group of 68 patients. Interestingly, a subgroup of these patients that was derived by including only patients with early and mild MS (N=23, median age 30 years, median Expanded Disability Status Scale =1.5, median duration 28 months) showed already cerebellar FA but no CBWM volume reductions. FA reductions were correlated with disability, atrophy, and disease duration. CONCLUSION: "Normal appearing" cerebellar white matter can be damaged in a very early stage of RRMS. DTI seems to be a sensitive tool for detecting this hidden cerebellar damage.

Deficits in tongue motor control are linked to microstructural brain damage in multiple sclerosis: a pilot study.

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.

Early and Degressive Putamen Atrophy in Multiple Sclerosis.

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.

FDG µPET Fails to Detect a Disease-Specific Phenotype in Rats Transgenic for Huntington's Disease ­ A 15 Months Follow-up Study.

BACKGROUND: FDG-PET detects hypometabolism in premanifest and symptomatic Huntington's disease (HD). A cross-sectional study suggested that whole-brain FDG-PET is capable to detect a phenotype in transgenic (tg) HD rats. Recently, a longitudinal follow-up study showed no FDG-PET changes in tgHD rats. Both studies applied small sample sizes and analysis was limited to whole-brain or striatum. OBJECTIVE: We therefore performed a follow-up study in a larger cohort of tgHD and wild-type (wt) rats encompassing several pre-defined regions of interest (ROIs) and hypothesis free voxel-by-voxel SPM analysis to clarify whether FDG-PET can detect a phenotype in tgHD rats and to determine onset …and effect sizes of changes over time. METHODS: N = 19 tgHD- and n = 20 wt-rats, mixed gender, were included. Repeated small animal FDG-µPET and MRI were performed at 5,10,15, and 20 months of age. ROIs encompassing entire brain, cortex, striatum, thalamus, subventricular-zone, and cerebellum were placed manually on the MRI and transferred to the co-registered µPET. Mean and maximal FDG-PET activities within ROIs were calculated and normalized to cerebellar FDG uptake. Activity and spatially normalized FDG-µPET were compared between groups on a hypothesis-free voxel-by-voxel basis using SPM. RESULTS: FDG uptake showed changes over time in both tgHD- and wt-rats, however, there was no consistent difference between tgHD- and wt-rats in both the manual ROI and SPM analysis. CONCLUSIONS: In this transgenic rat model of HD FDG-µPET imaging does not detect significant alterations at the ages investigated. Further investigations are warranted employing other age groups and alternative imaging biomarkers for neuronal degeneration, respectively.

Recovery of thalamic microstructural damage after Shiga toxin 2-associated hemolytic-uremic syndrome.

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 Stx2-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.

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor).

BACKGROUND: In light of the increased risk of progressive multifocal encephalopathy (PML) development under long-term treatment with the monoclonal antibody natalizumab which is approved for treatment of active relapsing remitting multiple sclerosis (RRMS), there is a clear need for alternative treatment options with comparable efficacy and reduced PML risk. One such option is fingolimod, a functional sphingosin-1-receptor antagonist that has been approved as first oral drug for treatment of active RRMS. However, the optimal switching design in terms of prevention of disease reoccurrence is still unknown. Moreover, potential additive effects of both drugs on immune functions, especially with regard to migration, have not yet been evaluated. METHODS/DESIGN: This is an exploratory, open-label, monocentric, investigator-initiated clinical trial. Fifteen RRMS patients under stable treatment with natalizumab will receive one last natalizumab infusion followed by a wash-out period of 8 weeks before fingolimod treatment initiation for a period of 24 weeks. Disease activity under natalizumab and during switching will be closely monitored by assessment of relapse rate and disease severity as well as high-frequent high-resolution magnetic resonance imaging including quantitative diffusion tensor imaging. Immunological assays include longitudinal assessment of adhesion molecule expression, functional evaluation of the migratory capacity of immune cells in an in-vitro model of the blood-brain-barrier, and the quality of cellular antiviral immune responses. DISCUSSION: Our trial represents the first detailed and longitudinal functional analysis of key immunological parameters in the process of switching from natalizumab and fingolimod, especially with regard to potential additive effects of both drugs on trafficking and immune surveillance. Moreover, our study will generate valuable information about even subtle disease exacerbations as consequence of natalizumab cessation, which will help to understand whether a switching protocol containing a wash-out period of 8 weeks before fingolimod treatment is appropriate in terms of disease stability.

Volume transition analysis: a new approach to resolve reclassification of brain tissue in repeated MRI scans.

BACKGROUND: Variability in brain tissue volumes derived from magnetic resonance images is attributable to various sources. In quantitative comparisons it is therefore crucial to distinguish between biologically and methodically conditioned variance and to take spatial accordance into account. NEW METHOD: We introduce volume transition analysis as a method that not only provides details on numerical and spatial accordance of tissue volumes in repeated scans but also on voxel shifts between tissue types. Based on brain tissue probability maps, mono- and bidirectional voxel shifts can be examined by explicitly separating volume transitions into source and target. We apply the approach to a set of subject data from repeated intra-scanner (one week and 30 month interval) as well as inter-scanner measurements. RESULTS: In all measurement scenarios, we found similar inter-class transitions of 9.9-15.9% of intracranial volume. The percentage of monodirectional net volume transition however increases from 0.3% in short term intra-scanner to 1.6% in long term intra-scanner and 9.3% in inter-scanner comparisons. COMPARISON WITH EXISTING METHODS: Unlike most routinely used variability measures volume transition analysis is able to monitor reclassifications and thus to quantify not only balanced flows but also the amount of monodirectional net flows between tissue classes. The approach is independent from group analysis and can thus be applied in as few as two images. CONCLUSIONS: The proposed method is an easily applicable tool that is useful in discovering intra-individual brain changes and assists in separating biological from technical variance in structural brain measures.

A human post-mortem brain model for the standardization of multi-centre MRI studies.

Multi-centre MRI studies of the brain are essential for enrolling large and diverse patient cohorts, as required for the investigation of heterogeneous neurological and psychiatric diseases. However, the multi-site comparison of standard MRI data sets that are weighted with respect to tissue parameters such as the relaxation times (T1, T2) and proton density (PD) may be problematic, as signal intensities and image contrasts depend on site-specific details such as the sequences used, imaging parameters, and sensitivity profiles of the radiofrequency (RF) coils. Water or gel phantoms are frequently used for long-term and/or inter-site quality assessment. However, these phantoms hardly mimic the structure, shape, size or tissue distribution of the human brain. The goals of this study were: (1) to validate the long-term stability of a human post-mortem brain phantom, performing quantitative mapping of T1, T2, and PD, and the magnetization transfer ratio (MTR) over a period of 18months; (2) to acquire and analyse data for this phantom and the brain of a healthy control (HC) in a multi-centre study for MRI protocol standardization in four centres, while conducting a voxel-wise as well as whole brain grey (GM) and white matter (WM) tissue volume comparison. MTR, T2, and the quotient of PD in WM and GM were stable in the post-mortem brain with no significant changes. T1 was found to decrease from 267/236ms (GM/WM) to 234/216ms between 5 and 17weeks post embedment, stabilizing during an 18-month period following the first scan at about 215/190ms. The volumetric measures, based on T1-weighted MP-RAGE images obtained at all participating centres, revealed inter- and intra-centre variations in the evaluated GM and WM volumes that displayed similar trends in both the post-mortem brain as well as the HC. At a confidence level of 95%, brain regions such as the brainstem, deep GM structures as well as boundaries between GM and WM tissues were found to be less reproducible than other brain regions in all participating centres. The results demonstrate that a post-mortem brain phantom may be used as a reliable tool for multi-centre MR studies.

Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer's disease.

In Alzheimer's disease, the contribution of inflammation is still controversially discussed. The aim of this study was to identify a particular immune profile in the peripheral blood (PB) and cerebrospinal fluid (CSF) in patients with mild Alzheimer's disease (mAD) and mild cognitive impairment (MCI) and its potential functional relevance and association with neurodegeneration. A total of 88 patients with cognitive decline (54 mAD, 19 MCI, and 15 other dementias) were included in this study and compared with a group of younger (mean age, 31.3 years) and older (mean age, 68.9 years) healthy volunteers. Patients underwent detailed neurologic and neuropsychological examination, magnetic resonance imaging including voxel-based morphometry of gray matter, voxel-based diffusion tensor imaging, and white matter lesion volumetry, and PB and CSF analysis including multiparameter flow cytometry. Multiparameter flow cytometry revealed that proportions of activated HLA-DR positive CD4(+) and CD8(+) T-cells were slightly and significantly increased in the PB of MCI and mAD patients, respectively, when compared with healthy elderly controls but not in patients with other dementias. Although only a slight enhancement of the proportion of activated CD4(+) T-cells was observed in the CSF of both MCI and mAD patients, the proportion of activated CD8(+) T-cells was significantly increased in the CSF of mAD patients when compared with healthy elderly individuals. A slight increase in the proportion of activated CD8(+) T-cells was also observed in the intrathecal compartment of MCI patients. Activation of cytotoxic CD8(+) T-cells was considerably related to AD-typical neuropsychological deficits. Voxel-based regression analysis revealed a significant correlation between CD8(+) T-cell activation and microstructural tissue damage within parahippocampal areas as assessed by diffusion tensor imaging. Taken together, peripheral and intrathecal CD8(+) T-cell activation in mAD was significantly different from other dementias, suggesting a specific adaptive immune response. Lymphocyte activation seems to have a clinical impact because levels of activated CD8(+) T-cells were correlated with clinical and structural markers of AD pathology.