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

Development and application of cerebral magnetic resonance elastography (MRE) for the mechanical characterisation of brain parenchyma in the context of neurodegenerative processes

Neurodegenerative Prozesse umfassen eine Vielzahl von Umbauvorgängen neuronalen Gewebes auf zellulärer und extrazellulärer Ebene. Neben typischen neurodegenerativen Erkrankungen wie dem Morbus Alzheimer oder der Multisystematrophie finden sich neurodegenerative Prozesse auch als Begleiterscheinung entzündlicher ZNS-Erkrankungen sowie als inhärentes Merkmal physiologischen Alterns. Eine Früherkennung mittels klinischer oder bildmorphologischer Parameter gelingt jedoch häufig nicht. Die Magnetresonanz- Elastographie (MRE) stellt eine struktursensitive Methode dar, deren Ziel die Analyse der viskoelastischen Eigenschaften des lebenden Gewebes ist. Pilotstudien haben eine hohe Sensitivität der MRE gegenüber neurodegenerativen Prozessen im gesunden alternden Gehirn sowie bei der schubförmig- remittierenden Multiplen Sklerose (rr-MS) gezeigt. Ziel dieser Arbeit war die systematische Untersuchung der Korrelation der viskoelastischen Eigenschaften des menschlichen Gehirns mit dem Alter, klinischen Parametern sowie bildmorphologischen Kenngrößen von Patienten mit chronisch progredienter MS (pp+sp-MS) und Normaldruckhydrozephalus (NPH) gegenüber gesunden Kontrollgruppen. Methodische Grundlage hierfür stellte die Mehrfrequenz-MRE dar, mit deren Hilfe zwei gewebemechanische Kenngrößen ermittelt wurden: (1) die Elastizität (μ) sowie (2) der viskoelastische Interpolationskoeffizient (α)- ein sensitiver Parameter für die Geometrie des mechanischen Netzwerkes. Ferner wurde die volumensensitive MRT zur Abgrenzung hirngeometrischer Veränderungen angewandt. Bezogen auf das Gesamthirn wurde eine signifikante altersabhängige Abnahme der Elastizität μ in einer Größenordnung von 0,75 % pro Jahr (P <0,001) gemessen, während die jährliche Volumenreduktion lediglich 0,23 % betrug. Weiterhin zeigte sich eine Abnahme der Elastizität um 20,5 % (P <0,001) bei pp+sp-MS sowie um 20,0 % (P <0,001) bei NPH im Vergleich zu altersentsprechenden Kontrollen. Demgegenüber fand sich in der alterskorrelierten Studie eine im Vergleich geringer erscheinende Reduktion des Interpolationsparameters α. Eine deutlichere Abnahme von α wurde bei Patienten mit pp+sp-MS (-6.1 % (P <0,001)) sowie bei NPH (-9 % (P <0,01)) beobachtet. Eine Shunt-Therapie bei NPH führte zu einem signifikanten Anstieg von α (P <0,001). Insgesamt stellen μ und α zwei unabhängige viskoelastische Materialparameter dar, welche aufgrund ihrer hohen Sensitivität gegenüber mechanischen Veränderungen der Gewebematrix des Gehirns zur Charakterisierung und Quantifizierung neurodegenerativer Prozesse geeignet erscheinen. Weitere Studien zur MRE bei neurodegenerativen Erkrankungen sind notwendig um den diagnostischen Wert der zerebralen MRE zu verifizieren.Neurodegeneration involves diverse tissue alterations on a cellular and extracellular level given by cell-loss, cell-shrinkage, neuronal remodeling and changes in the extracellular matrix. Apart from typical neurodegenerative diseases such as Alzheimer´s disease or multisystematrophy, chronic inflammatory diseases such as multiple sclerosis or even physiological aging can involve neurodegenerative processes. The detection of these processes by clinical and morphological image parameters especially at early stages is limited. Magnetic resonance elastography (MRE) represents a structure sensitive method based on the analysis of viscoelastic properties of biological tissue. Its reproducibility and high sensitivity towards neurodegenerative processes has been previously demonstrated in pilot studies. The aim of this thesis was the systematic analysis of the viscoelastic properties of the human brain and the correlation of mechanical parameters with age, clinical parameters and morphological image based markers of patients with chronic progressive multiple sclerosis (pp+sp-MS) and normal pressure hydrocephalus (NPH) compared to a healthy control group. Using multifrequency MRE two mechanical parameters can be acquired: (1) the elasticity (μ) and the powerlaw exponent (α)- a parameter sensitive towards the geometry of the mechanical network. The analysis of the brain´s volume was performed using standardized volume-sensitive MRI. An age-dependent reduction of elasticity by an annual decrease of 0.75 % (P <0.001) was observed while the annual decrease in brain volume was 0.23 % (P <0.001). The elasticity was reduced by 20.5 % (P <0.001) for patients with pp+sp-MS as well as 20.0 % (P <0.001) for patients with NPH in comparison to an age-matched control group. Interestingly, a significantly lower age-related reduction of the powerlaw exponent was observed, whereas pronounced decrease in α was found for patients with pp+sp-MS (-6.1 % (P <0.001)) and NPH (-9 % (P <0.001)). Approximately 90 days after shunt-treatment of NPH Patients α re-increased to unsymptomatic or physiological values. In conclusion, μ and α represent two independant viscoelastic parameters highly sensitive to structural changes of the mechanic tissue matrix. Therefore, cerebral MRE allows the non-invasive characterisation and quantification of neurodegenerative processes in vivo using MRE. Further studies for the verification of its diagnostic value are necessary

Regional variation in the parameter <i>α</i> representing the slope of the modulus dispersion and according to the springpot model.

<p>As <i>α</i> is sensitive to the microstructure geometry of biological tissue it is named ‘geometry’ parameter. Similar to <i>µ</i> (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0023451#pone-0023451-g003" target="_blank">Figure 3</a>), all regional differences are statistically significant (p<0.001).</p

Description of volume data and viscoelasticity parameters.

<p>The standard deviations (SD) are given in brackets.</p>a<p>dm³,</p>b<p>kPa.</p

Four image slices from T1-weighted volume MRI data compliant with MRE slice positions (upper row).

<p>Color-coded MRE wave data of 50 Hz vibrations. Blue colors scale vibrations towards the reader, while red to yellow colors scale motion beneath the image plane. The maximum tissue deflection is approximately 80<i> µ</i>m (mid row). Real-part modulus images corresponding to 50 Hz vibration frequency with specific regions of interest (ROIs) investigated in this study. Green lines: <i>ROI</i>_full, blue lines: <i>ROI</i>_inner, red lines: <i>ROI</i>_frontal, magenta lines: <i>ROI</i>_posterior, outer green lines excluding ventricles: <i>ROI</i>_full (bottom line).</p

Regional variation in the shear modulus of in vivo brain.

<p>All differences between the regions are statistically significant (p<0.001). The boxplot depicts the lower and upper quartiles as well as the median. Full data range (without outliers) is presented by whiskers. Crosses depict outliers.</p

Brain shear elasticity modulus averaged over the entire parenchyma visible in four image slices of all volunteers.

<p>Linear and quadratic regression is shown to indicate the order of softening of brain tissue with years of age.</p

Decrease in total brain volume and WM volume with age represented by linear regression of MRI volume data.

<p>Decrease in total brain volume and WM volume with age represented by linear regression of MRI volume data.</p

RBM3 and CIRP expressions in targeted temperature management treated cardiac arrest patients-A prospective single center study.

BACKGROUND:Management of cardiac arrest patients includes active body temperature control and strict prevention of fever to avoid further neurological damage. Cold-shock proteins RNA-binding motif 3 (RBM3) and cold inducible RNA-binding protein (CIRP) expressions are induced in vitro in response to hypothermia and play a key role in hypothermia-induced neuroprotection. OBJECTIVE:To measure gene expressions of RBM3, CIRP, and inflammatory biomarkers in whole blood samples from targeted temperature management (TTM)-treated post-cardiac arrest patients for the potential application as clinical biomarkers for the efficacy of TTM treatment. METHODS:A prospective single center trial with the inclusion of 22 cardiac arrest patients who were treated with TTM (33°C for 24 hours) after ROSC was performed. RBM3, CIRP, interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), and inducible nitric oxide synthase (iNOS) mRNA expressions were quantified by RT-qPCR. Serum RBM3 protein concentration was quantified using an enzyme-linked immunosorbent assay (ELISA). RESULTS:RBM3 mRNA expression was significantly induced in post-cardiac arrest patients in response to TTM. RBM3 mRNA was increased 2.2-fold compared to before TTM. A similar expression kinetic of 1.4-fold increase was observed for CIRP mRNA, but did not reached significancy. Serum RBM3 protein was not increased in response to TTM. IL-6 and MCP-1 expression peaked after ROSC and then significantly decreased. iNOS expression was significantly increased 24h after return of spontaneous circulation (ROSC) and TTM. CONCLUSIONS:RBM3 is temperature regulated in patients treated with TTM after CA and ROSC. RBM3 is a possible biomarker candidate to ensure the efficacy of TTM treatment in post-cardiac arrest patients and its pharmacological induction could be a potential future intervention strategy that warrants further research

Brain atrophy in MS patients.

<p>Significantly reduced brain parenchymal volume (<b>a</b>) and brain parenchymal fraction (BPF) (<b>b</b>) in MS patients compared to matched healthy individuals (*** P<0.001). The boxplots depict the lower and upper quartiles as well as the 50^th percentile (median). Full data range is presented by the whiskers. sp – secondary progressive, pp – primary progressive, rr – relapsing remitting.</p