Objective
Gray matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in multiple sclerosis (MS), but can these changes be ...identified in the patient early in the disease course?
Methods
To identify possible biomarkers linking meningeal inflammation, GM damage, and disease severity, gene and protein expression were analyzed in meninges and cerebrospinal fluid (CSF) from 27 postmortem secondary progressive MS and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T magnetic resonance imaging (MRI) were performed at diagnosis in 2 independent cohorts of MS patients (35 and 38 subjects) and in 26 non‐MS patients.
Results
Increased expression of proinflammatory cytokines (IFNγ, TNF, IL2, and IL22) and molecules related to sustained B‐cell activity and lymphoid‐neogenesis (CXCL13, CXCL10, LTα, IL6, and IL10) was detected in the meninges and CSF of postmortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar proinflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8, and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2, and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis.
Interpretation
A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at the time of diagnosis and at death. These results suggest a role for detailed CSF analysis combined with MRI as a prognostic marker for more aggressive MS. Ann Neurol 2018 Ann Neurol 2018;83:739–755
Ageing is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological ...process underlying ageing. Several stressors associated with ageing and MS pathology such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of CS. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with ageing and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression.
Multiple sclerosis is the major inflammatory condition affecting the central nervous system (CNS) and is characterised by disseminated focal immune-mediated demyelination. Demyelination is ...accompanied by variable axonal damage and loss and reactive gliosis. It is this pathology that is thought to be responsible for the clinical relapses that often respond well to immunomodulatory therapy. However, the later secondary progressive stage of MS remains largely refractory to treatment and it is widely suggested that accumulating axon loss is responsible for clinical progression. Although initially thought to be a white matter (WM) disease, it is increasingly apparent that extensive pathology is also seen in the grey matter (GM) throughout the CNS. GM pathology is characterised by demyelination in the relative absence of an immune cell infiltrate. Neuronal loss is also seen both in the GM lesions and in unaffected areas of the GM. The slow progressive nature of this later stage combined with the presence of extensive grey matter pathology has led to the suggestion that neurodegeneration might play an increasing role with increasing disease duration. However, there is a paucity of studies that have correlated the pathological features with clinical milestones during secondary progressive MS. Here, we review the contributions that the various types of pathology are likely to make to the increasing neurological deficit in MS.
Recent studies of cortical pathology in secondary progressive multiple sclerosis have shown that a more severe clinical course and the presence of extended subpial grey matter lesions with ...significant neuronal/glial loss and microglial activation are associated with meningeal inflammation, including the presence of lymphoid-like structures in the subarachnoid space in a proportion of cases.
To investigate the molecular consequences of pro-inflammatory and cytotoxic molecules diffusing from the meninges into the underlying grey matter, we carried out gene expression profiling analysis of the motor cortex from 20 post-mortem multiple sclerosis brains with and without substantial meningeal inflammation and 10 non-neurological controls.
Gene expression profiling of grey matter lesions and normal appearing grey matter not only confirmed the substantial pathological cell changes, which were greatest in multiple sclerosis cases with increased meningeal inflammation, but also demonstrated the upregulation of multiple genes/pathways associated with the inflammatory response. In particular, genes involved in tumour necrosis factor (TNF) signalling were significantly deregulated in MS cases compared with controls. Increased meningeal inflammation was found to be associated with a shift in the balance of TNF signalling away from TNFR1/TNFR2 and NFkB-mediated anti-apoptotic pathways towards TNFR1- and RIPK3-mediated pro-apoptotic/pro-necroptotic signalling in the grey matter, which was confirmed by RT-PCR analysis. TNFR1 was found expressed preferentially on neurons and oligodendrocytes in MS cortical grey matter, whereas TNFR2 was predominantly expressed by astrocytes and microglia.
We suggest that the inflammatory milieu generated in the subarachnoid space of the multiple sclerosis meninges by infiltrating immune cells leads to increased demyelinating and neurodegenerative pathology in the underlying grey matter due to changes in the balance of TNF signalling.
Four pyridines decorated with π-donating iminophosphorano substituents (R
PN-) in the 4-position were assessed as acylation catalysts. These catalysts display high sensitivity to the groups at ...phosphorus, with activities that are well correlated to the corresponding Hammett-type substituent constants (σ
), and can achieve superior activity over the most active dialkylamino-substituted pyridines. Iminophosphorano-substituted pyridines represent an easily accessible, tunable, and highly active class of nucleophilic organocatalysts.
Purpose
PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO ...radioligand
11
CPK-11195 limits accurate quantification.
18
FGE-180, a novel TSPO ligand, displays superior binding to
11
CPK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of
18
FGE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures.
Methods
Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of
18
FGE-180. Kinetic modelling of time–activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (
V
T
) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region.
Results
The two-tissue compartment model was the best model. The average regional delivery rate constant (
K
1
) was 0.01 mL cm
−3
min
−1
indicating low extraction across the blood–brain barrier (1 %). The estimated median
V
T
across all ROIs was also low, ranging from 0.16 mL cm
−3
in the striatum to 0.38 mL cm
−3
in the thalamus. There were no significant differences in
V
T
between HABs and MABs across all ROIs.
Conclusion
A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low
V
T
estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of
18
FGE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.
The resident macrophages of the central nervous system, microglia, are becoming increasingly implicated as active participants in neuropathology and ageing. Their diverse and changeable morphology is ...tightly linked with functions they perform, enabling assessment of their activity through image analysis. To better understand the contributions of microglia in health, senescence, and disease, it is necessary to measure morphology with both speed and reliability. A machine learning approach was developed to facilitate automatic classification of images of retinal microglial cells as one of five morphotypes, using a support vector machine (SVM). The area under the receiver operating characteristic curve for this SVM was between 0.99 and 1, indicating strong performance. The densities of the different microglial morphologies were automatically assessed (using the SVM) within wholemount retinal images. Retinas used in the study were sourced from 28 healthy C57/BL6 mice split over three age points (2, 6, and 28-months). The prevalence of 'activated' microglial morphology was significantly higher at 6- and 28-months compared to 2-months (p < .05 and p < .01 respectively), and 'rod' significantly higher at 6-months than 28-months (p < 0.01). The results of the present study propose a robust cell classification SVM, and further evidence of the dynamic role microglia play in ageing.
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