Differently from other myeloid cells, microglia derive exclusively from precursors originating within the yolk sac and migrate to the CNS under development, without any contribution from fetal liver ...or postnatal hematopoiesis. Consistent with their unique ontology, microglia may express specific physiological markers, which have been partly described in recent years. Here we wondered whether profiles distinguishing microglia from peripheral macrophages vary with age and under pathology. To this goal, we profiled transcriptomes of microglia throughout the lifespan and included a parallel comparison with peripheral macrophages under physiological and neuroinflammatory settings using age- and sex-matched wild-type and bone marrow chimera mouse models. This comprehensive approach demonstrated that the phenotypic differentiation between microglia and peripheral macrophages is age-dependent and that peripheral macrophages do express some of the most commonly described microglia-specific markers early during development, such as Fcrls, P2ry12, Tmem119, and Trem2. Further, during chronic neuroinflammation CNS-infiltrating macrophages and not peripheral myeloid cells acquire microglial markers, indicating that the CNS niche may instruct peripheral myeloid cells to gain the phenotype and, presumably, the function of the microglia cell. In conclusion, our data provide further evidence about the plasticity of the myeloid cell and suggest caution in the strict definition and application of microglia-specific markers.
Understanding the respective role of microglia and infiltrating monocytes in neuroinflammatory conditions has recently seemed possible by the identification of a specific microglia signature. Here instead we provide evidence that peripheral macrophages may express some of the most commonly described microglia markers at some developmental stages or pathological conditions, in particular during chronic neuroinflammation. Further, our data support the hypothesis about phenotypic plasticity and convergence among distinct myeloid cells so that they may act as a functional unit rather than as different entities, boosting their mutual functions in different phases of disease. This holds relevant implications in the view of the growing use of myeloid cell therapies to treat brain disease in humans.
Background:
Incidence and prevalence trends of multiple sclerosis (MS) in the Province of Padua, North-East Italy, suggest that environmental factors may be associated with increased MS risk.
...Objective:
To investigate the association of PM2.5 with MS prevalence in one of the most polluted geographical area of Italy.
Methods:
In total, 1435 Italian MS patients residing in the Province of Padua were enrolled. The province surface was classified into urban areas, isolated villages, industrialized places, and countryside. Satellite-derived dust-free and sea salt-free PM2.5 concentrations (annual average 1998–2015, μg/m3) allowed the identification of 18 classes of territorial sections with statistically evaluable numbers of inhabitants. Possible correlations between residential locality types, PM2.5 concentrations, and MS prevalence were investigated.
Results:
MS prevalence was significantly (p < 0.0001) higher in urban areas (ranging from 219 in Padua City to 169/100,000 in other urban areas) compared to isolated villages (116/100,000) or rural domains (109/100,000) and strongly correlated with the annual average concentration of PM2.5 (r = 0.81, p < 0.001). Regression analysis further associated MS cases with PM.2.5 average concentration (β = 0.11, p < 0.001).
Conclusion:
In the Province of Padua, MS prevalence is strongly associated with PM2.5 exposure suggesting that air pollutants may be one of the possible environmental risk factors for MS.
Microglia, the tissue resident macrophages of the brain, are increasingly recognized as key players for central nervous system development and homeostasis. They are long-lived cells deriving from a ...transient wave of yolk-sac derived erythro-myeloid progenitors early in development. Their unique ontology has prompted the search for specific markers to be used for their selective investigation and manipulation. The first generation of genome-wide expression studies has provided a bundle of transcripts (such as Olfml3, Fcrls, Tmem119, P2ry12, Gpr34, and Siglech) useful to distinguish microglia from peripheral macrophages. However, more recent reports have revealed that microglial phenotype is constantly shaped by the microenvironment in a time-, and context-dependent manner. In this article, we review data that provide additional pieces to this complex scenario and show the existence of unexpected phenotypic convergence between microglia and peripheral macrophages at certain developmental stages and under pathological conditions. These observations suggest that the two cell types act synergically boosting their mutual activities depending on the microenvironment. This novel information about the biology of microglia and peripheral macrophages sheds new light about their therapeutic potential for neuroinflammatory and neurodegenerative diseases.
Apart from IgG oligoclonal bands, no other biomarker has, to date, been validated for diagnostic and/or prognostic purposes in multiple sclerosis (MS).
To investigate a wide panel of cytokines and ...chemokines in the cerebrospinal fluid (CSF) of relapsing-remitting MS (RRMS) patients and evaluate their association with clinical and magnetic resonance imaging (MRI) parameters, as well as their predictive clinical value.
Fifty-one RRMS at clinical onset and 17 other not inflammatory neurological disorders (ONINDs) underwent brain MRI (including 3D-T1, 3D-FLAIR, and 3-DIR sequences) and CSF examination. Eighty-seven cytokines and chemokines were analyzed in CSF by Multiplex technology.
Compared to ONIND, CXCL-10, CXCL-11, CXCL-13, CCL-1, CCL-2, CCL-3, CCL-22, IL-16, and BAFF were significantly (
< 0.05) increased in RRMS CSF. However, only CCL-3 was associated with both MS diagnosis and IgGOB detection. Based on a 95%CI in ONIND (cut-off value: 0.798 pg/ml) and ROC analysis (cut-off value: 0.495 pg/ml), RRMS patients were stratified in CCL-3
(>0.736 pg/mL), CCL-3
, and CCL-3
(<0.495 pg/ml). Survival analysis disclosed a strong association between high CCL-3 values and disease reactivation (OR = 4.9, 95%CI: 1.8-13.3,
< 0.005) in the following 2 years.
CCL-3 deserves further investigation as a candidate prognostic biomarker for RRMS.
Abstract Spinal cord involvement associated with severe copper deficiency has been reported in the last 8 years. Copper deficiency may produce an ataxic myelopathy. Clinical and neuroimaging findings ...are similar to the subacute combined degeneration seen in patients with vitamin B12 deficiency. Macrocytic, normocytic and microcytic anemia, leukopenia and, in severe cases, pancytopenia are well known hematologic manifestations. The most patients with copper deficiency myelopathy had unrecognized carency. Some authors suggested that early recognition and copper supplementation may prevent neurologic deterioration but clinical findings do not improve. We present a patient with copper deficiency, dorsal root ganglions and cervical dorsal columns involvement. Clinical status and neuroimaging improved after copper replacement therapy. Sensory neurons of dorsal root ganglia may be the most sensitive nervous pathway. In this case the early copper treatment allowed to improve neurologic lesions and to prevent further involvements.
Microglia are observed in the early developing forebrain and contribute to the regulation of neurogenesis through still unravelled mechanisms. In the developing cerebral cortex, microglia cluster in ...the ventricular/subventricular zone (VZ/SVZ), a region containing Cxcl12-expressing basal progenitors (BPs). Here we show that the ablation of BP as well as genetic loss of Cxcl12 affect microglia recruitment into the SVZ. Ectopic Cxcl12 expression or pharmacological blockage of CxcR4 further supports that Cxcl12/CxcR4 signalling is involved in microglial recruitment during cortical development. Furthermore, we found that cell death in the developing forebrain triggers microglial proliferation and that this is mediated by the release of macrophage migration inhibitory factor (MIF). Finally, we show that the depletion of microglia in mice lacking receptor for colony-stimulating factor-1 (Csf-1R) reduces BPs into the cerebral cortex.
An association between frailty and vascular brain damage (VBD) has been described in older adults. However, most studies have identified frailty according to the phenotypic model. It is less clear ...whether frailty, operationalized as an accumulation of health deficits, is associated with the presence and severity of VBD. The present study was therefore undertaken to verify whether a 50-item frailty index (FI) is related to VBD in a large and relatively unselected cohort of attendees of a memory clinic.
The TREDEM (Treviso Dementia) registry includes retrospective observational data of 1584 participants. A modified FI was calculated from 50 variables comprising diseases, disability, behavioral disorders, and blood biochemistry. The presence and severity of VBD, including leukoaraiosis, lacunes, larger infarctions and the hierarchical vascular rating scale (HVRS), were determined based on brain computerized tomography imaging. Multiple logistic regression models were built according to the stepwise method.
Mean age of the 1584 participants was 79.6 ± 7.5 years and 1033 (65.2 %) were females. The average number of health deficits was 11.6 ± 6.2, corresponding to an FI of 0.23 ± 0.12 (range: 0.00–0.56). Each 0.01-point increase in the FI was associated with an increased probability of leukoaraiosis (+2.3 %) and severe leukoaraiosis (+5 %), lacunas in the basal ganglia (+1.73 %), occipital lobes (+2.7 %), parietal lobes (+3 %), frontal lobes (+3.6 %), temporal lobes (+4.2 %), and thalamus (+4.4 %). Moreover, an increase of 0.01 points in the FI was associated with a 3.1 % increase in the probability of HVRS score (≥2).
An FI based on routine clinical and laboratory variables was associated with the presence, degree, and some localizations of VBD in a population of older adults with cognitive decline. This frailty assessment tool may therefore be used to identify individuals at risk of developing cerebrovascular disease and, consequently, to implement strategies for vascular risk factor control.
•The frailty index (FI) provides a comprehensive overview of an individual's vulnerability.•The FI is positively correlated with the severity of vascular brain damage.•Study participants were relatively unselected outpatients and may therefore be representative of a “real-world” population.•The FI may be used to identity older adults at risk of cerebrovascular disease.
Abstract
The
18
F-FDG PET images of dementia with Lewy bodies and posterior cortical atrophy, a visual-cognitive phenotype described in patients with Alzheimer disease, show occipital lobe ...hypometabolism with relative sparing of the primary visual cortex (PVC) generating the “occipital tunnel” sign proposed by Sawyer and Kuo in 2017, which is viewable on the medial sagittal projection. We believe that the saving of PVC compared with the lateral occipital cortex can be better appreciated by capturing the posterior projection of the PVC in a 3D stereotactic surface projection map, and we propose the name of “occipital pole” sign for this evidence.
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Multiple sclerosis (MS) is a neurological disorder characterized by immune dysregulation. It begins with a first clinical manifestation, a clinically isolated syndrome (CIS), which ...evolves to definite MS in case of further clinical and/or neuroradiological episodes. Here we evaluated the diagnostic value of transcriptional alterations in MS and CIS blood by machine learning (ML).
Deep sequencing of more than 200 blood RNA samples comprising CIS, MS and healthy subjects, generated transcriptomes that were analyzed by the binary classification workflow to distinguish MS from healthy subjects and the Time-To-Event pipeline to predict CIS conversion to MS along time. To identify optimal classifiers, we performed algorithm benchmarking by nested cross-validation with the train set in both pipelines and then tested models generated with the train set on an independent dataset for final validation.
The binary classification model identified a blood transcriptional signature classifying definite MS from healthy subjects with 97% accuracy, indicating that MS is associated with a clear predictive transcriptional signature in blood cells. When analyzing CIS data with ML survival models, prediction power of CIS conversion to MS was about 72% when using paraclinical data and 74.3% when using blood transcriptomes, indicating that blood-based classifiers obtained at the first clinical event can efficiently predict risk of developing MS.
Coupling blood transcriptomics with ML approaches enables retrieval of predictive signatures of CIS conversion and MS state, thus introducing early non-invasive approaches to MS diagnosis.
The 18 F-FDG PET images of dementia with Lewy bodies and posterior cortical atrophy, a visual-cognitive phenotype described in patients with Alzheimer disease, show occipital lobe hypometabolism with ...relative sparing of the primary visual cortex (PVC) generating the "occipital tunnel" sign proposed by Sawyer and Kuo in 2017, which is viewable on the medial sagittal projection. We believe that the saving of PVC compared with the lateral occipital cortex can be better appreciated by capturing the posterior projection of the PVC in a 3D stereotactic surface projection map, and we propose the name of "occipital pole" sign for this evidence.
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