Increased serum glial fibrillary acidic protein associates with microstructural white matter damage in multiple sclerosis: GFAP and DTI

BackgroundAstrocytes and microglial cells are now recognized as active players in contributing to the diffuse neuroaxonal damage associated with disease progression of multiple sclerosis (MS). The serum level of glial fibrillary acidic protein (GFAP), a biomarker for astrocytic activation, is increased in MS and associates with disease progression and disability. Similarly, diffusion tensor imaging (DTI) parameters for microstructural changes in brain, including demyelination and axonal loss, associate with disability. The association between brain DTI parameters and serum GFAP has not been previously explored in MS. The objective of the study was to get insights into DTI-measurable pathological correlates of elevated serum GFAP in the normal appearing white matter (NAWM) of MS.MethodsA total of 62 MS patients with median age of 49.2 years were included in the study. Study patients underwent DTI-MRI and blood sampling for GFAP determination by single molecule array (Simoa). Mean fractional anisotropy (FA) and mean (MD), axial (AD) and radial (RD) diffusivities were calculated within the entire NAWM and six segmented NAWM regions. The associations between the DTI parameters and GFAP levels were analysed using Spearman correlation analysis and multiple regression model with sex and disease modifying treatment (no, 1st line or 2nd line) as adjustments.ResultsElevated serum GFAP levels correlated significantly with decreased FA values within the entire (ρ = -0.39, p = 0.03), frontal (ρ = -0.42, p = 0.02), temporal (ρ = -0.37; p = 0.04) and cingulate (ρ = -0.38, p = 0.034) NAWM, and increased MD and RD within the frontal NAWM (ρ = 0.36, p = 0.046 for both). Similarly, higher GFAP associated with lower FA in frontal and cingulate NAWM in the multiple regression model corrected for confounding variables (standardised regression coefficient β = -0.29, p = 0.045 and β = -0.33, p = 0.025).ConclusionsOur results give evidence that increased serum GFAP levels associate with DTI-measurable micro-damage in the NAWM in MS. Our work supports the use of serum GFAP as a biomarker for MS pathology-related astrocytopathy and related diffuse white matter damage.</p

High serum neurofilament associates with diffuse white matter damage in MS

Objective To evaluate to which extent serum neurofilament light chain (NfL) increase is related to diffusion tensor imaging-MRI measurable diffuse normal-appearing white matter (NAWM) damage in MS.Methods Seventy-nine patients with MS and 10 healthy controls underwent MRI including diffusion tensor sequences and serum NfL determination by single molecule array (Simoa). Fractional anisotropy and mean, axial, and radial diffusivities were calculated within the whole and segmented (frontal, parietal, temporal, occipital, cingulate, and deep) NAWM. Spearman correlations and multiple regression models were used to assess the associations between diffusion tensor imaging, volumetric MRI data, and NfL.Results Elevated NfL correlated with decreased fractional anisotropy and increased mean, axial, and radial diffusivities in the entire and segmented NAWM (for entire NAWM ρ = −0.49, p = 0.005; ρ = 0.49, p = 0.005; ρ = 0.43, p = 0.018; and ρ = 0.48, p = 0.006, respectively). A multiple regression model examining the effect of diffusion tensor indices on NfL showed significant associations when adjusted for sex, age, disease type, the expanded disability status scale, treatment, and presence of relapses. In the same model, T2 lesion volume was similarly associated with NfL.​​​​​​​Conclusions Our findings suggest that elevated serum NfL in MS results from neuroaxonal damage both within the NAWM and focal T2 lesions. This pathologic heterogeneity ought to be taken into account when interpreting NfL findings at the individual patient level.</p

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

Heparin Protects Human Neural Progenitor Cells from Zika Virus-Induced Cell Death While Preserving Their Differentiation into Mature Neuroglial Cells

Zika virus (ZIKV) is an arbovirus member of the Flaviviridae family that causes severe congenital brain anomalies in infected fetuses. The key target cells of ZIKV infection, human neural progenitor cells (hNPCs), are highly permissive to infection that causes the inhibition of cell proliferation and induces cell death. We have previously shown that pharmaceutical-grade heparin inhibits virus-induced cell death with negligible effects on in vitro virus replication in ZIKV-infected hNPCs at the "high" multiplicity of infection (MOI) of 1. Here, we show that heparin inhibits formation of ZIKV-induced intracellular vacuoles, a signature of paraptosis, and inhibits necrosis and apoptosis of hNPCs grown as neurospheres (NS). To test whether heparin preserved the differentiation of ZIKV-infected hNPCs into neuroglial cells, hNPCs were infected at the MOI of 0.001. In this experimental condition, heparin inhibited ZIKV replication by ca. 2 log10, mostly interfering with virion attachment, while maintaining its protective effect against ZIKV-induced cytopathicity. Heparin preserved differentiation into neuroglial cells of hNPCs that were obtained from either human-induced pluripotent stem cells (hiPSC) or by fetal tissue. Quite surprisingly, multiple additions of heparin to hNPCs enabled prolonged virus replication while preventing virus-induced cytopathicity. Collectively, these results highlight the potential neuroprotective effect of heparin that could serve as a lead compound to develop novel agents for preventing the damage of ZIKV infection on the developing brain. IMPORTANCE ZIKV is a neurotropic virus that invades neural progenitor cells (NPCs), causing inhibition of their proliferation and maturation into neurons and glial cells. We have shown previously that heparin, an anticoagulant also used widely during pregnancy, prevents ZIKV-induced cell death with negligible inhibition of virus replication. Here, we demonstrate that heparin also exerts antiviral activity against ZIKV replication using a much lower infectious inoculum. Moreover, heparin interferes with different modalities of virus-induced cell death. Finally, heparin-induced prevention of virus-induced NPC death allows their differentiation into neuroglial cells despite the intracellular accumulation of virions. These results highlight the potential use of heparin, or pharmacological agents derived from it, in pregnant women to prevent the devastating effects of ZIKV infection on the developing brain of their fetuses

Multimodal approach to the evaluation of diffuse neuroinflammation in multiple sclerosis using positron emission tomography and diffusion tensor imaging

Neuroinflammation, neurodegeneration and demyelination of brain, spinal cord and optic nerves are attributed to multiple sclerosis (MS) pathogenesis. Conventional magnetic resonance imaging (MRI) is mainly used for evaluation of inflammatory activity and diffuse atrophy in diagnosis and follow-up in MS. Diffusion tensor imaging (DTI) implementation makes it possible to reveal microstructural alterations in normal appearing white matter tracts, undetectable in conventional MRI. Positron emission tomography (PET) in vivo molecular imaging of activated microglia with translocator protein (TSPO) binding radioligand, provide additional information on the inflammatory activity in normal appearing white matter (NAWM) as well as in the differentiation between the chronic active and inactive MS lesion type. Combination of both imaging modalities will enable a better understanding of MS pathology and can possibly contribute to the prediction of a progressive course of the disease. The aim of this research was to evaluate structural and molecular brain changes using combined MR and PET in vivo imaging techniques in MS patients compared to healthy controls (HC), with correlational analyses of DTI data to TSPO-PET radioligand binding. The data of 55 MS patients with both RRMS (n = 40) and SPMS (n = 15) disease types and 15 healthy subjects were acquired from previously performed MS imaging studies in Turku PET Centre