Anatomically constrained tractography facilitates biologically plausible fiber reconstruction of the optic radiation in multiple sclerosis.

Diffusion-weighted magnetic resonance imaging (dMRI) enables the microstructural characterization and reconstruction of white matter pathways in vivo non-invasively. However, dMRI only provides information on the orientation of potential fibers but not on their anatomical plausibility. To that end, recent methodological advances facilitate the effective use of anatomical priors in the process of fiber reconstruction, thus improving the accuracy of the results. Here, we investigated the potential of anatomically constrained tracking (ACT), a modular addition to the tractography software package MRtrix3, to accurately reconstruct the optic radiation, a commonly affected pathway in multiple sclerosis (MS). Diffusion MRI data were acquired from 28 MS patients and 22 age- and sex-matched healthy controls. For each participant, the optic radiation was segmented based on the fiber reconstruction obtained using ACT. When implementing ACT in MS, it proved essential to incorporate lesion maps to avoid incorrect reconstructions due to tissue-type misclassifications in lesional areas. The ACT-based results were compared with those obtained using two commonly used probabilistic fiber tracking procedures, based on FSL (FMRIB Software Library) and MRtrix3 without ACT. All three procedures enabled a reliable localization of the optic radiation in both MS patients and controls. However, for FSL and MRtrix3 without ACT it was necessary to place an additional waypoint halfway between the lateral geniculate nucleus and the primary visual cortex to filter out anatomically implausible tracks. In the case of ACT, the results with and without an additional waypoint were virtually identical, presumably because the employed anatomical constraints already prevented the occurrence of the most implausible tracks. Irrespective of the employed tractography procedure, increased diffusivity and decreased anisotropy were found in the optic radiation of the MS patients compared to the controls.

Neuromyelitis optica and multiple sclerosis: Seeing differences through optical coherence tomography.

Neuromyelitis optica (NMO) is an inflammatory autoimmune disease of the central nervous system that preferentially targets the optic nerves and spinal cord. The clinical presentation may suggest multiple sclerosis (MS), but a highly specific serum autoantibody against the astrocytic water channel aquaporin-4 present in up to 80% of NMO patients enables distinction from MS. Optic neuritis may occur in either condition resulting in neuro-anatomical retinal changes. Optical coherence tomography (OCT) has become a useful tool for analyzing retinal damage both in MS and NMO. Numerous studies showed that optic neuritis in NMO typically results in more severe retinal nerve fiber layer (RNFL) and ganglion cell layer thinning and more frequent development of microcystic macular edema than in MS. Furthermore, while patients' RNFL thinning also occurs in the absence of optic neuritis in MS, subclinical damage seems to be rare in NMO. Thus, OCT might be useful in differentiating NMO from MS and serve as an outcome parameter in clinical studies.

Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria.

BACKGROUND: Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. OBJECTIVE: An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. METHODS: A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. RESULTS: The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. CONCLUSION: Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.

Loss of retinal nerve fibre layer axons indicates white but not grey matter damage in early multiple sclerosis.

BACKGROUND AND PURPOSE: Optical coherence tomography (OCT) has shown thinning of the retinal nerve fibre layer (RNFL) and total macular volume (TMV) in multiple sclerosis (MS) patients. Measures of retinal atrophy are associated with the brain parenchymal fraction (BPF) assessed by magnetic resonance imaging (MRI). However, in MS, data on the relation of OCT measures and grey and white matter volumes are contradictory. We performed a prospective cross-sectional study with a statistically pre-defined endpoint to test our hypothesis that OCT measures of neuro-axonal degeneration are related to global and partial brain atrophy in early forms of MS. METHODS AND RESULTS: Forty-four patients with clinically isolated syndrome (n = 10) or relapsing-remitting MS (n = 34; mean disease duration = 3.2 years, median EDSS = 1.5) were enrolled in the study. Peripapillary- and volumetric OCT scans of the macula were performed using latest spectral-domain OCT technology. BPF as well as white and grey matter fractions (WMF/GMF) were assessed by 1.5 Tesla MRI scans. Generalized estimating equation models adjusted for age and linear regression statistics were used to assess the association between OCT and MRI measures. RNFL thickness, TMV and age were significantly associated with BPF. RNFL thickness and TMV independently predicted WMF (P = 0.003 and P = 0.032) but not GMF (P = 0.717 and P = 0.357) when corrected for age. In contrast, age was strongly associated with GMF (P < 0.001) but not WMF. CONCLUSION: Our study suggests that, in early MS, OCT measures of retinal atrophy are related to volumetric changes in the white but not grey matter compartment as assessed by MRI. It further substantiates the association of retinal thinning and brain tissue loss in MS.

No proinflammatory signature in CD34+ hematopoietic progenitor cells in multiple sclerosis patients.

Autologous hematopoietic stem cell transplantation (aHSCT) has been used as a therapeutic approach in multiple sclerosis (MS). However, it is still unclear if the immune system that emerges from autologous CD34+ hematopoietic progenitor cells (HPC) of MS patients is pre-conditioned to re-develop the proinflammatory phenotype. The objective of this article is to compare the whole genome gene and microRNA expression signature in CD34+ HPC of MS patients and healthy donors (HD). CD34+ HPC were isolated from peripheral blood of eight MS patients and five HD and analyzed by whole genome gene expression and microRNA expression microarray. Among the differentially expressed genes (DEGs) only TNNT1 reached statistical significance (logFC=3.1, p<0.01). The microRNA expression was not significantly different between MS patients and HD. We did not find significant alterations of gene expression or microRNA profiles in CD34+ HPCs of MS patients. Our results support the use of aHSCT for treatment of MS.

Quantitative T2' imaging in patients with clinically isolated syndrome.

OBJECTIVE: The T2' imaging has been shown to be sensitive to oxygen saturation changes in normal appearing white and grey matter (NAWM, NAGM) in patients with relapsing-remitting multiple sclerosis (RRMS). We aimed to explore the presence and extent of T2' changes in patients with a clinically isolated syndrome (CIS) and a possible association of T2' with conventional magnetic resonance imaging and clinical outcomes. MATERIAL AND METHODS: Quantitative T2- and T2*-weighted images were acquired in 32 treatment-naive patients with a CIS within 3 months of presentation and 15 age-matched healthy controls (HC). Quantitative T2' values were determined in six regions of interest (ROIs). RESULTS: The T2' values in CIS did not differ significantly from those in HC. Among patients, T2' values correlated positively with the T2 lesion volume (T2LV, r = 0.34, P < 0.05). T2' values of the frontal NAWM correlated with the T2LV (r = 0.35, P < 0.05) and T2 lesion count (r = 0.4, P = 0.02). CONCLUSION: As opposed to RRMS, patients with CIS did not show T2' alterations compared to HC. However, the association between the T2LV and higher T2' values suggests that T2' reflects disease evolution. In CIS metabolic changes might be masked by compensatory mechanisms and become overt when disease progresses as has been shown for RRMS patients.

Accuracy of diagnostic tests in multiple sclerosis--a systematic review.

New diagnostic criteria for multiple sclerosis (MS) have been recently proposed and further updates are upcoming. This systematic literature review summarizes diagnostic studies in suspected MS to clarify the value of diagnostic tests. We included studies of at least 40 patients followed up for 2 years. All studies are limited by the fact that no gold standard to validate diagnostic tests is available. A second relapse is used as a surrogate in relapsing-remitting MS, but long follow-up of at least 5 years is necessary to detect all cases. Many studies showed selection bias, partly because of the vague definition of a clinically isolated syndrome. Based on these limitations, sensitivity of magnetic resonance imaging (MRI) criteria was between 35% and 100%, and specificity was between 36% and 92%. Cerebrospinal fluid (CSF) oligoclonal banding showed sensitivities between 69% and 91% with specificities between 59% and 94%. Combination studies of MRI and CSF indicate enhanced sensitivity (56-100%) and specificity (53-96%). Studies on evoked potentials did not justify conclusions about their value. A combination of simplified MRI criteria with CSF might be the best approach for an early MS diagnosis. However, the value of a very early diagnosis stays questionable as patients' benefit of new diagnostic criteria has never been addressed.

Inhibitory and facilitatory connectivity from ventral premotor to primary motor cortex in healthy humans at rest--a bifocal TMS study.

OBJECTIVE: In macaques, intracortical electrical stimulation of ventral premotor cortex (PMv) can modulate ipsilateral primary motor cortex (M1) excitability at short interstimulus intervals (ISIs). METHODS: Adopting the same conditioning-test approach, we used bifocal transcranial magnetic stimulation (TMS) to examine intrahemispheric connectivity between left PMv and M1 in humans. A conditioning stimulus (CS) was applied to PMv at intensities of 80% and 90% of active motor threshold (AMT) and 90% and 110% of resting motor threshold (RMT). A supra-threshold test stimulus (TS) was given 2, 4, 6, 8 and 10 ms after the CS and the amplitude of the motor evoked potential (MEP) was measured to probe corticospinal excitability. RESULTS: The CS facilitated corticospinal excitability in ipsilateral M1 when PMv was stimulated with 80% AMT 4 or 6 ms before the TS. At the same ISIs, the CS suppressed corticospinal excitability when the stimulus intensity was increased to 90% RMT. Conditioning effects were site-specific because conditioning the dorsal premotor cortex (PMd) at three different sites produced different effects. Using neuronavigated TMS the PMv site where applied CS produced changes in ipsilateral M1 excitability was located at the border between ventral Brodmann area (BA) 6 and BA 44, the human homologue of monkey's PMv (area F5). CONCLUSION: We infer that the corticospinal motor output from M1 to contralateral hand muscles can be facilitated or inhibited by a CS over ipsilateral PMv. SIGNIFICANCE: The fact that conditioning effects following PMd stimulation differ from those after PMv stimulation supports the concept that inputs from premotor cortices to M1 are functionally segregated.

T2' imaging indicates decreased tissue metabolism in frontal white matter of MS patients.

BACKGROUND AND PURPOSE: T2'-Magnetic resonance imaging (MRI) allows estimation of oxygen metabolism in normal appearing white and gray matter (NAWM and NAGM) and is sensitive to local iron deposition. We hypothesized that T2' imaging is feasible in routine use and reveals differences between MS patients and healthy subjects. METHODS: T2- and T2*-weighted images were acquired in 23 MS patients (Mean age: 36.8, range: 23-58 years) and 23 age-matched healthy subjects. Quantitative T2- and T2*-values were determined in six regions of interest (ROIs). RESULTS: The T2' values in thalamus and caudate nucleus were significantly lower in MS patients than in healthy subjects (139 ms vs 157 ms, P < 0.001 and 97 ms vs 115 ms, P < 0.01). The NAWM in the frontal lobe revealed significant higher T2' values than in healthy subjects (217 ms vs 170 ms, P < 0.001). The subcortical NAWM revealed significant lower T2' values than in healthy subjects (174 ms vs 187 ms, P < 0.028). CONCLUSION: T2' values differed significantly between MS patients and healthy subjects. The reduced T2' values in the basal ganglia are presumably related to higher iron concentration whereas the increased T2' in frontal NAWM most probably reflects reduced tissue metabolism. T2' imaging is feasible for routine-use and promising for monitoring therapy effects.

[Stem cell therapy in multiple sclerosis: a clinical update]. / Stammzelltherapie bei multipler Sklerose: Eine Bilanz aus klinischer Sicht.

Promising results in an animal model of multiple sclerosis (MS; experimental autoimmune encephalomyelitis, EAE) have shown that immunosuppression followed by allogeneic bone marrow transplantation has the potential to significantly ameliorate the spontaneous course of the disease. Since 1995, emerging data on autologous hematopoietic stem cell transplantation (AHSCT) has supported a benefit also in patients with multiple sclerosis. To date, results on approximately 500 cases have been consecutively reported by the European Group for Blood and Marrow Transplantation (EBMT). These reports have not only proved a favourable outcome for many patients but also provided the rationale for the currently ongoing controlled trials on AHSCT in MS. At present, results from the ASTIMS study in particular, a multicenter active-controlled phase II study, are awaited. However, a number of critical issues remain unresolved. Furthermore, with upcoming new treatment compounds that to some extent act via lymphoablative properties, it remains essential to better select those patients who might profit most from stem cell therapy based on a justifiable benefit-to-risk ratio. Although transplant related mortality has dropped to 1%, mortality combined with concerns about long-term safety remain critical issues in a primarily non-life-threatening disease like MS.

Early anisotropy changes in the corpus callosum of patients with optic neuritis.

INTRODUCTION: Optic neuritis (ON) and any other early manifestation of multiple sclerosis (MS) are referred to as clinically isolated syndrome (CIS) as long as MS is suspected. In this prospective study we aimed to determine whether diffusion tensor imaging (DTI) could quantify structural changes in patients with early MS. METHODS: A total of 24 patients and 15 control subjects were prospectively followed by clinical examinations and MRI. the main inclusion criterion was presentation with ON. Patients underwent serial MRI scans: MRI1 (baseline, n=24), MRI2 (mean 6.6 months, n=24), MRI3 (mean 13.0 months, n=14), MRI4 (mean 39.4 months, n=5). Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were derived from DTI. Four regions of interest (ROIs) were defined in normal-appearing white matter (NAWM). RESULTS: In the temporal course FA decreased in the genu of the callosal body (GCC) from MRI1 to MRI4 (P=0.005) and in the splenium of the callosal body (SCC) (P=0.006). Patients already had lower FA values in the SCC (P<0.01) on MRI1 compared with the controls. Patients had lower FA values in the GCC (P<0.01) starting from MRI2. Patients with definite MS on follow-up (n=9) showed a correlation between FA in the SCC and time (r=-0.40, P=0.004), whereas patients without progression did not. CONCLUSIONS: Our findings suggest that the corpus callosum is an early site for development of anisotropy changes in MS patients with ON. There seems to be a primary FA decrease in all patients with ON that only deteriorates in the group developing definite MS.

[Diagnosis and heterogeneity of MS in MRI]. / Bildmorphologie der Multiplen Sklerose als inflammatorische und degenerative Erkrankung: Diagnosesicherung und Heterogenität im Krankheitsverlauf.

An efficient therapy of MS requires a quick and reliable diagnosis of the disease. MRI is the most leading paraclinical examination for MS diagnosis. Even though there is no pathognomic finding in MRI, there are MS characteristics with respect to morphology and localization. To exclude other neurological disorders and distinguish between different characteristics within MS, the use of contrast agent is advantageous. Postulated MRI criteria have been increasingly adjusted to the clinical routine and have become clearer, more sensitive, and more specific. Different imaging criteria will be introduced. In addition to the McDonald criteria of 2001 and 2005, new criteria will be presented in which the use of contrast agent is replaced by a second MRI and the dissemination in time and space is simplified. Different pathomechanisms which help to separate MS patients into subgroups are postulated. The diverse pathomechanisms also enable the development of new pharmaceuticals to manipulate the immunologic course in different stages. For varying therapy approaches, it is increasingly important to differentiate the heterogeneous appearance forms into subtypes. The two visible main components of the disorder in MRI are inflammation and neurodegeneration and are responsible for different clinical courses. Both are interdependent and independent of each other. We introduce a stratification which uses both components as a function of their different outcomes to compose subgroups. The previous challenge with respect to MRI was to support the diagnosis of MS via MRI criteria. A future problem will be the heterogeneity and classification of subgroups. This article gives an overview of both problems.

Sensorimotor integration is abnormal in asymptomatic Parkin mutation carriers: a TMS study.

BACKGROUND: In patients with Parkinson disease (PD), transcranial magnetic stimulation (TMS) studies have consistently demonstrated a reduced inhibitory tone in the sensorimotor cortex. It remains unclear whether this is related to motor symptoms or represents adaptive compensatory changes to degeneration of dopaminergic neurons. Here we used short-interval afferent inhibition after digital stimulation (dSAI) and intracortical paired-pulse inhibition and facilitation to probe intracortical sensorimotor excitability in clinically asymptomatic carriers of a single mutant Parkin allele who have a latent nigrostriatal dopaminergic dysfunction. METHODS: Nine heterozygous mutation carriers and nine healthy controls were investigated. For dSAI testing, electrical pulses were applied to the right index finger followed by TMS pulses over the left motor cortex at interstimulus intervals (ISI) of 25, 30, and 40 msec. Intracortical paired-pulse excitability was tested at ISIs of 2 to 15 msec. RESULTS: dSAI was reduced at an ISI of 25 msec in carriers of a single mutant Parkin allele, whereas paired-pulse TMS was normal. CONCLUSION: The relative decrease in sensorimotor inhibition may be a direct consequence of the Parkin mutation or represent adaptive changes at the cortical level in response to a subcortical dysfunction, but is not caused by motor symptoms.

Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma.

Amyloid-beta (Abeta) peptide, a major constituent of senile plaques and a hallmark of Alzheimer's disease (AD), is normally secreted by neurons and can be found in low concentrations in cerebrospinal fluid (CSF) and plasma, where it is associated with lipoproteins. However, the physiological role of Abeta secretion remains unknown. Here we show that at the concentrations measured in biological fluids (0.1-1.0 nM), Abeta(1-40) strongly inhibits autooxidation of CSF lipoproteins and plasma low density lipoprotein (LDL). At higher concentrations of the peptide its antioxidant action was abolished. Abeta(1-40) also inhibited copper-catalyzed LDL oxidation when added in molar excess of copper, but did not influence oxidation induced by an azo-initiator. Other Abeta peptides also possessed antioxidant activity in the order Abeta(1-40) > Abeta(1-42) > Abeta(25-35), whereas Abeta(35-25) was inactive. These data suggest that Abeta(1-40) may act as a physiological antioxidant in CSF and plasma lipoproteins, functioning by chelating transition metal ions.

Increased lipoprotein oxidation in Alzheimer's disease.

Oxidation has been proposed to be an important factor in the pathogenesis of Alzheimer's disease (AD) and amyloid beta is considered to induce oxidation. In biological fluids, including cerebrospinal fluid (CSF), amyloid beta is found complexed to lipoproteins. On the basis of these observations, we investigated the potential role of lipoprotein oxidation in the pathology of AD. Lipoprotein oxidizability was measured in vitro in CSF and plasma from 29 AD patients and found to be significantly increased in comparison to 29 nondemented controls. The levels of the hydrophilic antioxidant ascorbate were significantly lower in CSF and plasma from AD patients. In plasma, alpha-carotene was significantly lower in AD patients compared to controls while alpha-tocopherol levels were indistinguishable between patients and controls. In CSF, a nonsignificant trend to lower alpha-tocopherol levels among AD patients was found. Polyunsaturated fatty acids, the lipid substrate for oxidation, were significantly lower in the CSF of AD patients. Our findings suggest that (i) lipoprotein oxidation may be important in the development of AD and (ii) the in vitro measurement of lipid peroxidation in CSF might become a useful additional marker for diagnosis of AD.

Plasma ubiquinol-10 as a marker for disease: is the assay worthwhile?

Ubiquinol-10 and ubiquinone-10 were measured in plasma of patients with several pathologies known to be associated with increased oxidative stress. Plasma ubiquinol-10, expressed as a percentage of total ubiquinol-10 + ubiquinone-10, was found to be significantly lower in hyperlipidaemic patients and in patients with liver diseases than in age-matched control subjects. In contrast, no decrease in ubiquinol-10 was detected in plasma of patients with coronary heart disease and Alzheimer's disease. Except for ubiquinol-10, no other lipophilic antioxidant was found to be decreased in patients with liver diseases. These data suggest that the level of ubiquinol-10 in human plasma may serve as a marker for liver dysfunction, reflecting its diminished reduction by the liver rather than increased consumption by oxidants.