Brain viscoelasticity alteration in chronic-progressive multiple sclerosis

Introduction

Viscoelastic properties indicate structural alterations in biological tissues at multiple scales with high sensitivity. Magnetic Resonance Elastography (MRE) is a novel technique that directly visualizes and quantitatively measures biomechanical tissue properties in vivo. MRE recently revealed that early relapsing-remitting multiple sclerosis (MS) is associated with a global decrease of the cerebral mechanical integrity. This study addresses MRE and MR volumetry in chronic-progressive disease courses of MS.

Methods

We determined viscoelastic parameters of the brain parenchyma in 23 MS patients with primary or secondary chronic progressive disease course in comparison to 38 age- and gender-matched healthy individuals by multifrequency MRE, and correlated the results with clinical data, T2 lesion load and brain volume. Two viscoelastic parameters, the shear elasticity μ and the powerlaw exponent α, were deduced according to the springpot model and compared to literature values of relapsing-remitting MS.

Results

In chronic-progressive MS patients, μ and α were reduced by 20.5% and 6.1%, respectively, compared to healthy controls. MR volumetry yielded a weaker correlation: Total brain volume loss in MS patients was in the range of 7.5% and 1.7% considering the brain parenchymal fraction. All findings were significant (P<0.001).

Conclusions

Chronic-progressive MS disease courses show a pronounced reduction of the cerebral shear elasticity compared to early relapsing-remitting disease. The powerlaw exponent α decreased only in the chronic-progressive stage of MS, suggesting an alteration in the geometry of the cerebral mechanical network due to chronic neuroinflammation.     

Efficacy of vision restoration therapy after optic neuritis (VISION study): study protocol for a randomized controlled trial

Background

One of the main causes of mortality and morbidity following subarachnoid haemorrhage (SAH) is the development of cerebral vasospasm, a frequent complication arising in the weeks after the initial bleeding. Despite extensive research, to date no effective treatment of vasospasm exists. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. In vitro models have shown a relaxing effect of prostacyclin after induced contraction in cerebral arteries, and a recent pilot trial showed a positive effect on cerebral vasospasm in a clinical setting. No randomised, clinical trials have been conducted, investigating the possible pharmacodynamic effects of prostacyclin on the human brain following SAH.

Methods

This trial is a single-centre, randomised, placebo-controlled, parallel group, blinded, clinical, pilot trial. A total of 90 patients with SAH will be randomised to one of three intervention arms: epoprostenol 1?ng/kg/min, epoprostenol 2?ng/kg/min or placebo in addition to standard treatment. Trial medication will start day 5 after SAH and continue to day 10. The primary outcome measure is changes in regional cerebral blood flow from baseline in the arterial territories of the anterior cerebral artery, medial cerebral artery and the posterior cerebral artery, measured by CT perfusion scan. The secondary outcomes will be vasospasm measured by CT angiography, ischaemic parameters measured by brain microdialysis, flow velocities in the medial cerebral artery, clinical parameters and outcome (Glasgow Outcome Scale) at 3?months.

Trial registration

Clinicaltrials.gov NCT01447095.     

Temporal retinal nerve fiber loss in patients with spinocerebellar ataxia type 1

Background

Autosomal dominant spinocerebellar ataxia type 1 is an adult onset progressive disorder with well characterized neurodegeneration in the cerebellum and brainstem. Beyond brain atrophy, few data exist concerning retinal and optic nerve involvement.

Objective

To evaluate retinal changes in SCA1 patients compared to age and gender matched healthy controls.

Methodology/Principal Findings

Nine patients with SCA1 were prospectively recruited from the ataxia clinic and were compared to nine age and gender matched healthy controls. Both cohorts received assessment of visually evoked potentials and eye examination by optical coherence tomography to determine retinal nerve fiber layer thickness and total macular volume. While no differences were found in visually evoked potentials, SCA1 patients showed a significant reduction of mean retinal nerve fiber layer thickness (RNFLT) compared to healthy controls (84±13 µm vs. 97±8 µm, p = 0.004). Temporal areas showed the most prominent RNFLT reduction with high statistical significances (temporal-inferior: p<0.001, temporal: p<0.001, temporal-superior: p = 0.005) whereas RNFLT in nasal areas was in the range of the control group. From six SCA1 patients an additional macular scan was obtained. The comparison to the corresponding healthy control showed a slight but not significant reduction in TMV (8.22±0.68 mm³ vs. 8.61±0.41 mm³, p = 0.15).

Conclusion

In SCA1 patients, we found evidence for degeneration of retinal nerve fibers. The temporal focus of the observed retinal nerve fiber layer reduction suggests an involvement of the papillo-macular bundle which resembles pathology found in toxic or mitochondrial optic nerve disease such as Leber''s hereditary optic neuropathy (LHON) or dominant optic atrophy (DOA).     

Inhibition of glycogen synthase kinase-3β counteracts ligand-independent activity of the androgen receptor in castration resistant prostate cancer

In order to generate genomic signals, the androgen receptor (AR) has to be transported into the nucleus upon androgenic stimuli. However, there is evidence from in vitro experiments that in castration-resistant prostate cancer (CRPC) cells the AR is able to translocate into the nucleus in a ligand-independent manner. The recent finding that inhibition of the glycogen-synthase-kinase 3β (GSK-3β) induces a rapid nuclear export of the AR in androgen-stimulated prostate cancer cells prompted us to analyze the effects of a GSK-3β inhibition in the castration-resistant LNCaP sublines C4-2 and LNCaP-SSR. Both cell lines exhibit high levels of nuclear AR in the absence of androgenic stimuli. Exposure of these cells to the maleimide SB216763, a potent GSK-3β inhibitor, resulted in a rapid nuclear export of the AR even under androgen-deprived conditions. Moreover, the ability of C4-2 and LNCaP-SSR cells to grow in the absence of androgens was diminished after pharmacological inhibition of GSK-3β in vitro. The ability of SB216763 to modulate AR signalling and function in CRPC in vivo was additionally demonstrated in a modified chick chorioallantoic membrane xenograft assay after systemic delivery of SB216763. Our data suggest that inhibition of GSK-3β helps target the AR for export from the nucleus thereby diminishing the effects of mislocated AR in CRPC cells. Therefore, inhibition of GSK-3β could be an interesting new strategy for the treatment of CRPC.     

Strength of word-specific neural memory traces assessed electrophysiologically

Memory traces for words are frequently conceptualized neurobiologically as networks of neurons interconnected via reciprocal links developed through associative learning in the process of language acquisition. Neurophysiological reflection of activation of such memory traces has been reported using the mismatch negativity brain potential (MMN), which demonstrates an enhanced response to meaningful words over meaningless items. This enhancement is believed to be generated by the activation of strongly intraconnected long-term memory circuits for words that can be automatically triggered by spoken linguistic input and that are absent for unfamiliar phonological stimuli. This conceptual framework critically predicts different amounts of activation depending on the strength of the word's lexical representation in the brain. The frequent use of words should lead to more strongly connected representations, whereas less frequent items would be associated with more weakly linked circuits. A word with higher frequency of occurrence in the subject's language should therefore lead to a more pronounced lexical MMN response than its low-frequency counterpart. We tested this prediction by comparing the event-related potentials elicited by low- and high-frequency words in a passive oddball paradigm; physical stimulus contrasts were kept identical. We found that, consistent with our prediction, presenting the high-frequency stimulus led to a significantly more pronounced MMN response relative to the low-frequency one, a finding that is highly similar to previously reported MMN enhancement to words over meaningless pseudowords. Furthermore, activation elicited by the higher-frequency word peaked earlier relative to low-frequency one, suggesting more rapid access to frequently used lexical entries. These results lend further support to the above view on word memory traces as strongly connected assemblies of neurons. The speed and magnitude of their activation appears to be linked to the strength of internal connections in a memory circuit, which is in turn determined by the everyday use of language elements.     

Patients' and observers' perceptions of involvement differ. Validation study on inter-relating measures for shared decision making

Objective

Patient involvement into medical decisions as conceived in the shared decision making method (SDM) is essential in evidence based medicine. However, it is not conclusively evident how best to define, realize and evaluate involvement to enable patients making informed choices. We aimed at investigating the ability of four measures to indicate patient involvement. While use and reporting of these instruments might imply wide overlap regarding the addressed constructs this assumption seems questionable with respect to the diversity of the perspectives from which the assessments are administered.

Methods

The study investigated a nested cohort (N = 79) of a randomized trial evaluating a patient decision aid on immunotherapy for multiple sclerosis. Convergent validities were calculated between observer ratings of videotaped physician-patient consultations (OPTION) and patients'' perceptions of the communication (Shared Decision Making Questionnaire, Control Preference Scale & Decisional Conflict Scale).

Results

OPTION reliability was high to excellent. Communication performance was low according to OPTION and high according to the three patient administered measures. No correlations were found between observer and patient judges, neither for means nor for single items. Patient report measures showed some moderate correlations.

Conclusion

Existing SDM measures do not refer to a single construct. A gold standard is missing to decide whether any of these measures has the potential to indicate patient involvement.

Practice Implications

Pronounced heterogeneity of the underpinning constructs implies difficulties regarding the interpretation of existing evidence on the efficacy of SDM. Consideration of communication theory and basic definitions of SDM would recommend an inter-subjective focus of measurement.

Trial Registration

Controlled-Trials.com ISRCTN25267500.