Jan Debruyne

PET visualization of microglia in multiple sclerosis patients using [11C] PK11195

Activated microglia are involved in the immune response of multiple sclerosis (MS). The peripheral benzodiazepine receptor (PBR) is expressed on microglia and up‐regulated after neuronal injury. [11C]PK11195 is a positron emission tomography (PET) radioligand for the PBR. The objective of the present study was to investigate [11C]PK11195 imaging in MS patients and its additional value over magnetic resonance imaging (MRI) concerning the immuno‐pathophysiological process. Seven healthy and 22 MS subjects were included. Semiquantitative [11C]PK11195 uptake values were assessed with normalization on cortical grey matter. Uptake in Gadolinium‐lesions was significantly increased compared with normal white matter. Uptake in T2‐lesions was generally decreased, suggesting a PBR down‐regulation. However, uptake values increased whenever a clinical or MR‐relapse was present, suggestive for a dynamic process with a transient PBR up‐regulation. During disease progression, an increase of normal‐appearing white matter (NAWM) uptake was found, propagating NAWM as the possible real burden of disease. In conclusion, [11C]PK11195 and PET are able to demonstrate inflammatory processes with microglial involvement in MS.

Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis : a correlative study

Objective: The objectives of the present study were to assess brain atrophy in multiple sclerosis (MS) patients during different disease stages and to investigate by PET and [11C]PK11195, a marker of microglial activation, the relationship between inflammation, atrophy and clinically relevant measures. Methods: Eight healthy subjects and 22 MS patients were included. Semiquantitative [11C]PK11195 uptake values, with normalization on cortical grey matter, were measured for magnetic resonance imaging T2- and T1-lesions and normal appearing white matter (NAWM). As atrophy index we used the ratio of the amount of white and grey matter divided by the ventricular size, using an optimized a priori based segmentation algorithm (SPM99). Results: Atrophy was significantly greater in MS patients compared to age-matched controls. A significant correlation was found between brain atrophy and both disease duration and disability, as measured with the Expanded Disability Status Scale. For NAWM, [11C]PK11195 uptake increased with the amount of atrophy, while T2-lesional [11C]PK11195 uptake values decreased according to increasing brain atrophy. Conclusions: The present study suggests that brain atrophy, correlating with disease duration and disability, is directly related to NAWM and T2-lesional inflammation as measured by microglial activation.

Risks of multiple sclerosis in relatives of patients in Flanders, Belgium.

OBJECTIVES: To calculate age adjusted risks for multiple sclerosis in relatives of Flemish patients with multiple sclerosis. METHODS: Lifetime risks were calculated using the maximum likelihood approach. RESULTS: Vital information was obtained on 674 probands with multiple sclerosis in Flanders and a total of their 26225 first, second, and third degree relatives. Full medical information to allow documentation of multiple sclerosis status was available for 21351 (81.4%) relatives. The age adjusted risk for parents was 1.61 (SEM 0.35)%, for siblings 2.10 (SE 0.36)%, and for children 1.71 (SEM 0.70)%. For aunts and uncles, the risk was 0.66 (SEM 0.13)%. CONCLUSIONS: The risk for first degree relatives of patients with multiple sclerosis in Flanders is increased 10-fold to 12-fold; for second degree relatives, it is increased threefold. This information can be used for risk counselling in families and provides additional support for the role of more than one locus contributing to the susceptibility of multiple sclerosis.

White-matter astrocytes, axonal energy metabolism, and axonal degeneration in multiple sclerosis

In patients with multiple sclerosis (MS), a diffuse axonal degeneration occurring throughout the white matter of the central nervous system causes progressive neurologic disability. The underlying mechanism is unclear. This review describes a number of pathways by which dysfunctional astrocytes in MS might lead to axonal degeneration. White-matter astrocytes in MS show a reduced metabolism of adenosine triphosphate-generating phosphocreatine, which may impair the astrocytic sodium potassium pump and lead to a reduced sodium-dependent glutamate uptake. Astrocytes in MS white matter appear to be deficient in β2 adrenergic receptors, which are involved in stimulating glycogenolysis and suppressing inducible nitric oxide synthase (NOS2). Glutamate toxicity, reduced astrocytic glycogenolysis leading to reduced lactate and glutamine production, and enhanced nitric oxide (NO) levels may all impair axonal mitochondrial metabolism, leading to axonal degeneration. In addition, glutamate-mediated oligodendrocyte damage and impaired myelination caused by a decreased production of N-acetylaspartate by axonal mitochondria might also contribute to axonal loss. White-matter astrocytes may be considered as a potential target for neuroprotective MS therapies.

In vitro TNF-α, IL-2 and IFN-γ production as markers of relapses in multiple sclerosis

In 22 patients with definite multiple sclerosis (MS) we determined with monthly intervals over a period of 24 months the in vitro tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-2 (IL-2) production and the serum neopterin levels. The results were compared with normative data collected from 14 healthy controls over the same period. Twenty-nine relapses in 13 patients were noticed. We found increased in vitro TNF-α production from 4 weeks on prior to the day of an exacerbation. There was a significant correlation with in vitro IFN-γ release, the absolute blood monocyte count and the serum neopterin levels, suggesting that monocytes stimulated by IFN-γ play an important role in the TNF-α production. Serial analysis of in vitro TNF-α production proved to be a helpful tool in predicting relapses in MS patients. Furthermore, elevated levels of IFN-γ and IL-2 after stimulation with OKT3 during exacerbations were demonstrated. Serial analysis of these two biological markers revealed to be of no value in predicting relapses.

Diffusion weighted callosal integrity reflects interhemispheric communication efficiency in multiple sclerosis.

We aimed to investigate the relation between damage in the corpus callosum and the performance on an interhemispheric communication task in patients with multiple sclerosis (MS). Relative callosal lesion load defined as the ratio between callosal area and the total lesion load in the total corpus callosum, and the diffusion tensor imaging (DTI) derived measures fractional anisotropy (FA) and transverse and longitudinal diffusivity were calculated in sixteen female MS patients and sixteen age and education matched female controls. The redundancy gain task was used to behaviorally evaluate interhemispheric communication efficiency. During this task, simple reaction times to uni- and bilateral presented stimuli are recorded. The advantage in reaction time for bilateral as compared to unilateral trials, the redundancy gain, was significantly larger for the MS-group. The DTI data showed significantly decreased FA and increased diffusivity parameters in the corpus callosum for the MS patients compared with the control group. Moreover, we found a significant correlation between the DTI-derived measures in the corpus callosum and the redundancy gain effect. Callosal damage in MS, as measured by DTI and defined as transverse diffusivity, is associated with alterations in a behavioral task that relies on interhemispheric transfer and communication.

Transverse Diffusivity of Cerebral Parenchyma Predicts Visual Tracking Performance in Relapsing-Remitting Multiple Sclerosis.

This study investigated the relation between cerebral damage related to multiple sclerosis (MS) and cognitive decline as determined by two classical mental tracking tests. Cerebral damage in 15 relapsing-remitting MS patients was measured by diffusion tensor imaging (DTI). Fractional anisotropy, longitudinal and transverse diffusivity were defined in the cerebral parenchyma. Cognitive performance of the MS patients was assessed with the oral response format of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT). A significant correlation was found between performance on the SDMT and the fractional anisotropy in the brain. This correlation was predominantly induced by transverse diffusivity. Transverse diffusivity refers to the diffusion across fibers rather than along the fibers and is believed to be a specific marker for axonal loss and demyelination associated with MS. No significant association between DTI-measures and PASAT performance was found and this negative finding was mainly attributed to psychometric qualities. These results indicate that diffusivity along the non-principal diffusion direction, a possible signature of MS-related white matter pathology, contributes to information processing speed as measured with the SDMT, a task that requires close visual tracking and a widely used clinical marker for cognitive decline in MS.

Relapse markers in multiple sclerosis: are in vitro cytokine production changes reflected by circulatory T-cell phenotype alterations?

In vitro tumor necrosis factor-a (TNF-a), interferon-g (IFN-g) and interleukin-2 (IL-2) production, serum neopterin levels, and T-lymphocyte subpopulations were determined on a monthly basis in 22 MS patients. We found increased in vitro TNF-a production from 4 weeks on prior to the day of an exacerbation. There was a significant correlation with in vitro IFN-g release, the absolute blood monocyte count and the serum neopterin levels, suggesting that monocytes stimulated by IFN-g play an important role in the TNF-a production. Serial analysis of in vitro TNF-a production proved to be a helpful tool in predicting relapses in MS patients. Furthermore, elevated levels of IFN-g and IL-2 after stimulation with OKT3 during exacerbations were demonstrated. These increases were not reflected by changes in T-lymphocyte subpopulations. However, significant differences in T-cell subsets were observed between controls and relapsing progressive patients.

False perception of visual verticality in multiple sclerosis

We wanted to investigate to what extent patients with multiple sclerosis (MS), not complaining of dizziness or disequilibrium, may have problems with the estimation of gravidity. Therefore, we studied the static ‘subjective visual vertical’ (SVV), a test that is thought to reflect mainly otolith function. Further, we correlated SVV measures with the degree of disease disability. A group of outpatients was compared with a group of age‐ and sex‐matched healthy volunteers. The deviations of SVV in patients were significantly larger than in controls. Overall, SVV was abnormal in 48% of individual patients. There was a significant correlation between SVV and the global disability score. The same held true for correlation with the subscores of brainstem and cerebellar complaints. The SVV test proved to be a simple method that was well tolerated by the patients. It can be considered a complementary otoneurological tool for evaluating MS patients. Further, these findings suggest that misperception of the verticality parallels the disability in MS patients.

Callosal function in MS patients with mild and severe callosal damage as reflected by diffusion tensor imaging.

In this study, callosal function was behaviourally tested in MS patients with a redundant stimuli task. Reaction times to uni- and bilateral visual stimuli are recorded. Normal subjects respond faster to bilateral than to unilateral stimuli. This effect is called the redundancy gain effect. In patients with agenesis of the corpus callosum, the redundancy gain exceeds that predicted by probability summation, suggesting a mediating influence of the corpus callosum in healthy controls. The aim of this study is to investigate the effect of callosal damage on the redundancy gain in MS patients by investigating the probability summation model. Seventeen MS patients and as many matched healthy controls performed the redundancy gain task. In order to objectify callosal damage in our MS group, diffusion tensor imaging (DTI) derived measures such as fractional anisotropy (FA) and mean diffusivity (MD) in the corpus callosum were obtained. Callosal FA and MD significantly differed in our MS group compared to the healthy controls, indicating pathological callosal involvement. Since the amount of callosal damage was highly variable within the MS group, the MS cohort was split into a low and a high callosal-injured group as quantified by FA. The high FA group performed like the healthy controls, whereas violations of the probability (race) model were found for the low FA group. We conclude that behavioural measures obtained by the redundancy gain paradigm reflect callosal pathology in MS as measured by DTI.