Development of biomarkers for multiple sclerosis as a neurodegenerative disorder

Multiple sclerosis (MS) is the most common neurological disorder leading to permanent disability in young adults in the developed world. While traditionally conceived as an autoimmune inflammatory disease it is becoming increasingly evident that axonal and neuronal degeneration occur, at least partly independent of inflammation, and already at the earliest stages of the disease. In addition, it is the progressive neurodegeneration which determines the amount of accumulating clinical disability. Therefore, MS should be considered as a neurodegenerative disorder. Development of disease-modifying drugs to treat MS is currently highly dynamic. Already, several drugs have shown short-term efficacy to delay progression of clinical disability, but the ultimate aim is to halt disease progression. In this context, the development of sensitive, reliable and valid biomarkers to measure neurodegeneration is an indispensible need to facilitate successful informative clinical trials. While no such biomarker is currently fully established, several promising candidate biomarkers obtained with multimodal techniques, including cerebrospinal fluid and serum analysis, neuroimaging and neurophysiology, are presently developed and evaluated. This paper compiles an up-to-date critical review of the available knowledge of candidate biomarkers of neurodegenerative processes in MS.     

Novel fibroblastic onion bulbs in a demyelinating avian peripheral neuropathy produced by riboflavin deficiency

Aquaporin-4 (AQP4) has recently been implicated in the pathogenesis of neuromyelitis optica (NMO) where it has been identified as the first defined autoantigen pertinent to an inflammatory demyelinating disorder of the human CNS. Furthermore, a recent case report has shown a lack of AQP4 expression in the spinal cord lesions of NMO. However, the pattern of AQP4 expression in multiple sclerosis (MS) tissues has not been well-defined. In the present investigation we have confirmed a lack of expression of AQP4 in optic and spinal cord lesions in NMO which contrasted sharply with the increased levels of AQP4 expression seen in MS lesions. Furthermore a detailed immunohistochemical and semi-quantitative analysis is used to describe the expression pattern of AQP4 on well-characterized tissue microarray samples of MS and control white matter. Anatomically AQP4 was more highly expressed in all categories of MS tissue compared to normal control tissues with the most abundant expression in active lesions. Within active lesions AQP4 expression was significantly correlated with expression of the pro-inflammatory cytokine osteopontin. At the cellular level dual-labeling immunofluoresence demonstrated that increased expression of AQP4 was most pronounced at the astrocytic endfeet but was also associated with the cell bodies of astrocytes in the tissue parenchyma. The finding of increased AQP4 expression in MS lesions in contrast to the lack of expression in NMO lesions may suggest different mechanisms of initiation and progression between the two disease states.     

Astrocytic β2-adrenergic receptors: From physiology to pathology

Evidence accumulates for a key role of the β₂-adrenergic receptors in the many homeostatic and neuroprotective functions of astrocytes, including glycogen metabolism, regulation of immune responses, release of neurotrophic factors, and the astrogliosis that occurs in response to neuronal injury. A dysregulation of the astrocytic β₂-adrenergic-pathway is suspected to contribute to the physiopathology of a number of prevalent and devastating neurological conditions such as multiple sclerosis, Alzheimer's disease, human immunodeficiency virus encephalitis, stroke and hepatic encephalopathy. In this review we focus on the physiological functions of astrocytic β₂-adrenergic receptors, and their possible impact in disease states.     

In vivo assessment of tumor heterogeneity in WHO 2016 glioma grades using diffusion kurtosis imaging: Diagnostic performance and improvement of feasibility in routine clinical practice

Purpose

To assess the diagnostic performance of normalized and non-normalized diffusion kurtosis imaging (DKI) metrics extracted from different tumor volume data for grading glioma according to the integrated approach of the revised 2016 WHO classification.

Diffusion tensor imaging for characterizing white matter changes in multiple sclerosis

Purpose

To investigate the diagnostic values of quantitative diffusion tensor imaging parameters in detecting abnormalities in white matter of MS patients and correlate this with lesion load and clinical disability as prognostic factors.

Patients and methods

Diffusion tensor imaging (DTI) was performed in 45 consecutive MS patients and 20 age-matched healthy control volunteers from March 2011 to November 2013. Mean diffusivity (MD), volume ratio (VR) and the fractional anisotropy (FA) were measured in normal appearing white matter (NAWM) and in different types of focal MS lesions during both activity and remission and compared with normal white matter (NWM) of the control group. Evaluation of lesion load was done by the semiautomated method. Clinical assessment of MS was established using the Kurtzke expanded disability status scale (EDSS) and the Kurtzke functional system score.

Results

Significant increase of MD and decrease of FA and VR from normal appearing white matter of the patients to MRI detected active lesions and the least is inactive plaques comparing with NWM of the control group (P value 0.003 for MD, 0.013 for FA, and 0.014 for VR). Correlation and significant difference between {(increase in MD) and (decrease in FA and VR)} and lesion load (strongest in parietal lobes) and also Kurtzke expanded disability status scale (EDSS) and Kurtzke functional system score (KFS-p).

Conclusion

DTI–MRI quantitative parameters are good predictors of tissue damage not only in MRI-defined lesions but also in NAWM as a result of Wallerian degeneration and are helpful as diagnostic and prognostic tools.     

Conventional and advanced MRI in multiple sclerosis

Magnetic resonance imaging (MRI) plays a central role in the management of patients with multiple sclerosis (MS). T2-weighted/FLAIR lesions have been included in the diagnostic criteria since 2001, and the importance of the technology has been expanded in each successive revision of the McDonald criteria. While the typical focal hyperintense lesions seen on T2 and FLAIR sequences in several areas of the central nervous system are key features for MS diagnosis, they can also be used to monitor disease activity, particularly in asymptomatic patients, and to evaluate therapeutic responses. The development of new lesions, particularly in medullary and infratentorial locations, is a strong predictor of long-term disability and risk of evolution to a secondary-progressive phase. Yet, changes in T2 lesion volume are poor predictors of subsequent disease evolution in many cases, a situation often referred to as the “clinicoradiological paradox”. Nevertheless, advanced MRI techniques allow quantification of several pathological processes in vivo and offer insights into MS pathophysiology beyond white matter lesions. By investigating what is happening beneath the visible surface of MS pathology, these techniques not only help to unravel the clinicoradiological paradox, but also provide early measures of functional and structural tissue abnormalities before the advent of irreversible neurodegeneration.     

Added value of double inversion recovery magnetic resonance sequence in detection of cortical and white matter brain lesions in multiple sclerosis

Objective

The aim of this study was to evaluate the value of double inversion recovery (DIR) magnetic resonance (MR) sequence in the detection of brain cortical and white matter lesions in multiple sclerosis (MS).

Patients and methods

Fifteen patients with remitting relapsing MS were included in this study. Imaging was performed on a 1.T MR system using DIR, fluid-attenuated inversion-recovery (FLAIR), and T2-weighted image (T2WI) sequences. The sensitivity of DIR was compared with the corresponding sensitivity of FLAIR and T2WI sequences. The contrast between lesions and normal-appearing gray matter (NAGM), normal-appearing white matter (NAWM), and cerebrospinal fluid (CSF) was determined for all sequences.

Results

DIR showed significantly more MS lesion load overall when compared to T2WI or FLAIR. Significantly higher number of lesions was seen in the supra- and infratentorial locations. DIR detected higher periventricular white matter lesions when compared to FLAIR, but did not detect significantly higher lesions when compared to T2WI. Significantly higher deep white matter, juxtacortical, and intracortical lesions were seen on DIR when compared to both T2WI and FLAIR. The image contrast measurements between the MS lesions and the NAWM in all anatomical locations were significantly higher in DIR sequence compared to both T2WI and FLAIR sequences. However, there was no significant statistical difference between the DIR and both T2WI and FLAIR sequences regarding the contrast of intracortical lesions compared to NAGM.

Conclusion

DIR sequence is valuable in the imaging workup of MS as it can detect more MS lesions compared to the T2W and FLAIR sequences in all anatomical locations. DIR showed better delineation between the white matter, gray matter, and the MS lesions due to its high image contrast. DIR sequence should be included in the routine MR protocol of MS patients especially to answer the question about intra-cortical and juxta-cortical MS lesions.     

1H‐MR spectroscopy and diffusion tensor imaging of normal‐appearing temporal white matter in patients with nasopharyngeal carcinoma after irradiation: Initial experience

Purpose:

To detect radiation‐induced changes of temporal lobe normal‐appearing white mater (NAWM) following radiation therapy (RT) for nasopharyngeal carcinoma (NPC).

Materials and Methods:

Seventy‐five H¹‐MR spectroscopy and diffusion‐tensor imaging (DTI) examinations were performed in 55 patients before and after receiving fractionated radiation therapy (total dose; 66–75GY). We divided the dataset into six groups, a pre‐RT control group and five other groups based on time after completion of RT. N‐acetylaspartic acid (NAA)/choline (Cho), NAA/creatine (Cr), Cho/Cr, mean diffusibility (MD), functional anisotropy (FA), radial diffusibility (λ_?), and axial diffusibility (λ_||) were calculated.

Results:

NAA/Cho and NAA/Cr decreased and λ_? increased significantly within 1 year after RT compared with pre‐RT. After 1 year, NAA/Cho, NAA/Cr, and λ_? were not significantly different from pre‐RT. In all post‐RT groups, FA decreased significantly. λ_|| decreased within 9 months after RT compared with pre‐RT, but was not significantly different from pre‐RT more than 9 months after RT.

Conclusion:

DTI and H¹‐MR spectroscopy can be used to detect early radiation‐induced changes of temporal lobe NAWM following radiation therapy for NPC. Metabolic alterations and water diffusion characteristics of temporal lobe NAWM in patients with NPC after RT were dynamic and transient. J. Magn. Reson. Imaging 2013;37:101–108. © 2012 Wiley Periodicals, Inc.

     

Weekly follow up of acute lesions in three early multiple sclerosis patients using MR spectroscopy and diffusion

Object

Pathophysiological mechanisms underlying multiple sclerosis (MS) lesion formation, including inflammation, demyelination/remyelination and axonal damage, and their temporal evolution are still not clearly understood. To this end, three acute white matter lesions were monitored using a weekly multimodal magnetic resonance (MR) protocol.