Evaluation of microglial activation in multiple sclerosis patients using positron emission tomography

Understanding the mechanisms underlying progression in multiple sclerosis (MS) is one of the key elements contributing to the identification of appropriate therapeutic targets for this under-managed condition. In addition to plaque-related focal inflammatory pathology typical for relapsing remitting MS there are, in progressive MS, widespread diffuse alterations in brain areas outside the focal lesions. This diffuse pathology is tightly related to microglial activation and is co-localized with signs of neurodegeneration. Microglia are brain-resident cells of the innate immune system and overactivation of microglia is associated with several neurodegenerative diseases. Understanding the role of microglial activation in relation to developing neurodegeneration and disease progression may provide a key to developing therapies to target progressive MS. 18-kDa translocator protein (TSPO) is a mitochondrial molecule upregulated in microglia upon their activation. Positron emission tomography (PET) imaging using TSPO-binding radioligands provides a method to assess microglial activation in patients in vivo. In this mini-review, we summarize the current status of TSPO imaging in the field of MS. In addition, the review discusses new insights into the potential use of this method in treatment trials and in clinical assessment of progressive MS.</p

Sex-driven variability in TSPO-expressing microglia in MS patients and healthy individuals

Background: Males with multiple sclerosis (MS) have a higher risk for disability progression than females, but the reasons for this are unclear.Objective: We hypothesized that potential differences in TSPO-expressing microglia between female and male MS patients could contribute to sex differences in clinical disease progression.Methods: The study cohort consisted of 102 MS patients (mean (SD) age 45.3 (9.7) years, median (IQR) disease duration 12.1 (7.0–17.2) years, 72% females, 74% relapsing–remitting MS) and 76 age- and sex-matched healthy controls. TSPO-expressing microglia were measured using the TSPO-binding radioligand [11C](R)-PK11195 and brain positron emission tomography (PET). TSPO-binding was quantified as distribution volume ratio (DVR) in normal-appearing white matter (NAWM), thalamus, whole brain and cortical gray matter (cGM).Results: Male MS patients had higher DVRs compared to female patients in the whole brain [1.22 (0.04) vs. 1.20 (0.02), p = 0.002], NAWM [1.24 (0.06) vs. 1.21 (0.05), p = 0.006], thalamus [1.37 (0.08) vs. 1.32 (0.02), p = 0.008] and cGM [1.25 (0.04) vs. 1.23 (0.04), p = 0.028]. Similarly, healthy men had higher DVRs compared to healthy women except for cGM. Of the studied subgroups, secondary progressive male MS patients had the highest DVRs in all regions, while female controls had the lowest DVRs.Conclusion: We observed higher TSPO-binding in males compared to females among people with MS and in healthy individuals. This sex-driven inherent variability in TSPO-expressing microglia may predispose male MS patients to greater likelihood of disease progression.<br/

Rituximab in the treatment of multiple sclerosis in the Hospital District of Southwest Finland

BackgroundThere are already numerous B-cell depleting monoclonal anti-CD20 antibodies which have been used to reduce the inflammatory burden associated with multiple sclerosis (MS). We describe here our experience of treating MS-patients with B-cell depleting rituximab.Patients and methodsAll MS-patients (n = 72) who had received rituximab treatment for at least six months by January 2019 were identified from the patient charts at the Turku University Hospital. Information about MS disease subtype, disease severity, MR-imaging outcomes and B-cell counts were collected from the charts.ResultsRituximab was well received and well tolerated by the patients. There were no serious infusion-related side effects. The most serious adverse event that led to treatment discontinuation was neutropenia. After rituximab initiation the annual number of relapses was decreased in the relapsing remitting and secondary progressive MS groups and the mean number of gadolinium-enhancing lesions was decreased in relapsing remitting MS. Our study confirms the usability of rituximab treatment for MS in the Finnish health care environment.ConclusionsOff-label rituximab-treatment can be successfully used to reduce MS disease burden for the benefit of MS patients.</div

Frequency and etiology of acute transverse myelitis in Southern Finland

Objective: Acute transverse myelitis is a relatively rare, frequently debilitating but potentially treatable emergency. The objective of this study was to evaluate the incidence and etiology of acute transverse myelitis in two major hospital districts in Southern Finland.Methods: We identified all patients with acute transverse myelitis admitted to Turku University Hospital and Päijät-Häme Central hospital during nine years. The two hospitals serve a catchment area of 673,000 people in Southern Finland. Acute transverse myelitis was diagnosed according to the 2002 Transverse Myelitis Consortium Working Group. Patient files were reviewed for details of the clinical presentation and disease outcome, for laboratory findings and for neuroimaging. Charts were re-evaluated after an average of 7.7 years for confirmation of the acute transverse myelitis etiology.Results: In total 63 patients fulfilled the Transverse Myelitis Consortium Working Group diagnostic criteria for acute transverse myelitis. The frequency of the condition was hence 1.04 cases/ 100,000 inhabitants/ year. In the studied cohort, 7/63 (11%) patients had idiopathic transverse myelitis after initial evaluation and in 4/63 (6.3%) patients the idiopathic transverse myelitis remained the final diagnosis after follow-up and re-evaluation. Of the disease-associated myelitis cases MS or clinically isolated syndrome was the largest group, explaining 41% of all myelitis cases. The mean follow-up time before a patient was diagnosed with MS was 1.7 ± 2.2 years. Other etiologies included acute disseminated encephalomyelitis (ADEM), neurosarcoidosis, neuromyelitis optica (NMO), systemic autoimmune diseases and infectious diseases.Conclusions: In more than half of the acute transverse myelitis cases the final diagnosis is other than MS. Careful diagnostic work-up is needed for correct early treatment and best long-term outcome.</p

Phenotyping of multiple sclerosis lesions according to innate immune cell activation using TSPO-PET

Abstract Chronic active lesions are promotors of neurodegeneration and disease progression in multiple sclerosis. They harbour a dense rim of activated innate immune cells at the lesion edge, which promote lesion growth and thereby induce damage. Conventional MRI is of limited help in identifying the chronic active lesions, so alternative imaging modalities are needed. Objectives were to develop a PET-based automated analysis method for phenotyping of chronic lesions based on lesion-associated innate immune cell activation and to comprehensively evaluate the prevalence of these lesions in the various clinical subtypes of multiple sclerosis, and their association with disability. In this work we use TSPO-PET-imaging for phenotyping chronic multiple sclerosis lesions at large scale. For this, we identified 1510 white matter T1-hypointense lesions from 91 multiple sclerosis patients [67 relapsing-remitting, 24 secondary progressive]. Innate immune cell activation at the lesion rim was measured using PET-imaging and the TSPO-binding radioligand 11C-PK11195. A T1-hypointense lesion was classified as rim-active if the distribution volume ratio of 11C-PK11195-binding was low in the plaque core and considerably higher at the plaque edge. If no significant ligand-binding was observed, the lesion was classified as inactive. Plaques that had considerable ligand-binding both in the core and at the rim were classified as overall-active. Conventional MRI and disability assessment using Expanded Disability Status Scale were performed at the time of PET-imaging. In the secondary progressive cohort, an average of 19% (median, interquartile range 11-26) of T1 lesions were rim-active in each individual patient, compared to 10% (interquartile range 0-20) among relapsing remitting patients (P = 0.009). Secondary progressive patients had a median of 3 (range 0-11) rim-active lesions, vs. 1 (range 0-18) among relapsing remitting patients (P = 0.029). Among those patients who had rim-active lesions (n = 63) the average number of active voxels at the rim was higher among secondary progressive compared to relapsing remitting patients (median 158 versus 74; P = 0.022). The number of active voxels at the rim correlated significantly with Expanded Disability Status Scale (R = 0.43, P <0.001), and the volume of the rim-active lesions similarly correlated with Expanded Disability Status Scale (R = 0.45, P < 0.001). Our study is the first to report in vivo phenotyping of chronic lesions at large scale, based on TSPO-PET. Patients with higher disability displayed a higher proportion of rim-active lesions. The in vivo lesion phenotyping methodology offers a new tool for individual assessment of smouldering (rim-active) lesion burden

Innate Immune Cell-Related Pathology in the Thalamus Signals a Risk for Disability Progression in Multiple Sclerosis

Background and Objectives Our aim was to investigate whether 18-kDa translocator protein (TSPO) radioligand binding in gray matter (GM) predicts later disability progression in multiple sclerosis (MS). Methods In this prospective imaging study, innate immune cells were investigated in the MS patient brain using PET imaging. The distribution volume ratio (DVR) of the TSPO-binding radioligand [C-11]PK11195 was determined in 5 GM regions: thalamus, caudate, putamen, pallidum, and cortical GM. Volumetric brain MRI parameters were obtained for comparison. The Expanded Disability Status Scale (EDSS) score was assessed at baseline and after follow-up of 3.0 +/- 0.3 (mean +/- SD) years. Disability progression was defined as an EDSS score increase of 1.0 point or 0.5 point if the baseline EDSS score was >= 6.0. A forward-type stepwise logistic regression model was constructed to compare multiple imaging and clinical variables in their ability to predict later disability progression. Results The cohort consisted of 66 patients with MS and 18 healthy controls. Patients with later disability progression (n = 17) had more advanced atrophy in the thalamus, caudate, and putamen at baseline compared with patients with no subsequent worsening. TSPO binding was significantly higher in the thalamus among the patients with later worsening. The thalamic DVR was the only measured imaging variable that remained a significant predictor of disability progression in the regression model. The final model predicted disability progression with 52.9% sensitivity and 93.9% specificity with an area under the curve value of 0.82 (receiver operating characteristic curve). Discussion Increased TSPO radioligand binding in the thalamus has potential in predicting short-term disability progression in MS and seems to be more sensitive for this than GM atrophy measures.</p

Serum glial fibrillary acidic protein correlates with multiple sclerosis disease severity

BACKGROUND:: Cerebrospinal fluid (CSF) levels of two soluble biomarkers, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), have been shown to associate with multiple sclerosis (MS) disease progression. Now, both biomarkers can be detected reliably in serum, and importantly, their serum levels correlate well with their CSF levels.OBJECTIVE:: To evaluate the usability of serum GFAP measurement as a biomarker of progressive disease and disease severity in MS.METHODS:: Clinical course, Expanded Disability Status Scale (EDSS), disease duration, patient age and magnetic resonance imaging (MRI) parameters were reviewed in 79 MS patients in this cross-sectional hospital-based study. Serum samples were collected for measurement of GFAP and NfL concentrations using single molecule array (Simoa) assay. A cohort of healthy controls was evaluated for comparison.RESULTS:: Higher serum concentrations of both GFAP and NfL were associated with higher EDSS, older age, longer disease duration, progressive disease course and MRI pathology.CONCLUSION:: Earlier studies have demonstrated that GFAP, unlike NfL, is not increased in association with acute focal inflammation-related nervous system damage. Our work suggests that GFAP serum level associates with disease progression in MS and could potentially serve as an easily measurable biomarker of central nervous system (CNS) pathology related to disease progression in MS.</p

Monoklonaaliset vasta-aineet MS-taudin hoidossa

English summaryPeer reviewe

Insights into disseminated MS brain pathology with multimodal diffusion tensor and PET imaging

Objective To evaluate in vivo the co-occurrence of microglial activation and microstructural white matter (WM) damage in the MS brain and to examine their association with clinical disability.Methods 18-kDa translocator protein (TSPO) brain PET imaging was performed for evaluation of microglial activation by using the radioligand [11C](R)-PK11195. TSPO binding was evaluated as the distribution volume ratio (DVR) from dynamic PET images. Diffusion tensor imaging (DTI) and conventional MRI (cMRI) were performed at the same time. Mean fractional anisotropy (FA) and mean (MD), axial, and radial (RD) diffusivities were calculated within the whole normal-appearing WM (NAWM) and segmented NAWM regions appearing normal in cMRI. Fifty-five patients with MS and 15 healthy controls (HCs) were examined.Results Microstructural damage was observed in the NAWM of the MS brain. DTI parameters of patients with MS were significantly altered in the NAWM compared with an age- and sex-matched HC group: mean FA was decreased, and MD and RD were increased. These structural abnormalities correlated with increased TSPO binding in the whole NAWM and in the temporal NAWM (p Conclusions Widespread structural disruption in the NAWM is linked to neuroinflammation, and both phenomena associate with clinical disability. Multimodal PET and DTI allow in vivo evaluation of widespread MS pathology not visible using cMRI.</div

The effect of prenatal maternal stress on the hypothalamuspituitary- adrenal axis of the child at the age of 6 months

Introduction: Prenatal environment has been associated with fetal development. Stress during pregnancy might lead to child’s increased risk for adverse outcomes such as cardiovascular diseases, behavioural problems and mental health problems later in life. The mechanisms mediating these adverse outcomes are not fully understood but it is thought that the underlying mechanism could be the alterations that prenatal maternal stress causes to the stress regulatory systems. Hypothalamus-pituitary-adrenal (HPA) axis is the main stress regulation system in humans, which regulates the production and release of glucocorticoids, in human cortisol, from the adrenal cortex into circulation. Glucocorticoids are important in the fetal development. Prenatal stress might expose the children for excess amount of endogenous glucocorticoids and thus the stress might affect the development and function of the HPA-axis. It is also possible that prenatal exposure to maternal medications such as synthetic corticosteroids or selective serotonin reuptake inhibitors (SSRIs) may affect the child HPA-axis development. The aim of the study was to evaluate the effect of prenatal stress and maternal medication to the function of the HPA-axis of the child at the age of 6 months. Methods: In total 185 children withdrawn from the FinnBrain Birth Cohort Study at the age of 6 months entered the case-control study. 79 of the subjects had been exposed to prenatal stress. Maternal prenatal stress was evaluated at the gestational weeks 14, 24 and 34, and 3 and 6 months postpartum with standardized questionnaires for depressive, overall anxiety, and pregnancy-related anxiety symptoms (EPDS, SCL-90 and PRAQ-R2). HPA-axis function was evaluated measuring basal cortisol concentration from saliva sample collected at the study visit. Information about the long-term medications of the mother was obtained with questionnaires at the gestational weeks 14 and 34 and 6 months postpartum. Results: Prenatal stress was associated with elevated basal cortisol only in girls. Increased baseline cortisol of the girls was also linked with overall anxiety during the early pregnancy. In addition, prenatal depression during the mid-gestation was related to higher cortisol baseline in the prenatal stress exposed children. Overall anxiety at 6 months postpartum was associated with increased basal cortisol in prenatal stress exposed children but decreased basal cortisol in boys. Exposure to maternal thyroxine medication during the early pregnancy was linked with elevated basal cortisols and postnatal exposure to hormonal contraceptives via breastfeeding resulted in lower basal cortisol in girls only. Conclusions: Prenatal stress and maternal medication affected especially the HPA-axis of the girls. The results refer that the HPA-axis of the girls may be more susceptible to prenatal medication and stress effects