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Stroke Aug 2020Cilostazol, a phosphodiesterase 3' inhibitor, is used in Asia-Pacific countries for stroke prevention, but rarely used elsewhere. In addition to weak antiplatelet... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND PURPOSE
Cilostazol, a phosphodiesterase 3' inhibitor, is used in Asia-Pacific countries for stroke prevention, but rarely used elsewhere. In addition to weak antiplatelet effects, it stabilizes endothelium, aids myelin repair and astrocyte-neuron energy transfer in laboratory models, effects that may be beneficial in preventing small vessel disease progression.
METHODS
A systematic review and meta-analysis of unconfounded randomized controlled trials of cilostazol to prevent stroke, cognitive decline, or radiological small vessel disease lesion progression. Two reviewers searched for papers (January 1, 2019 to July 16, 2019) and extracted data. We calculated Peto odds ratios (ORs) and 95% CIs for recurrent ischemic, hemorrhagic stroke, death, adverse symptoms, with sensitivity analyses. The review is registered (CRD42018084742).
RESULTS
We included 20 randomized controlled trials (n=10 505), 18 in ischemic stroke (total n=10 449) and 2 in cognitive impairment (n=56); most were performed in Asia-Pacific countries. Cilostazol decreased recurrent ischemic stroke (17 trials, n=10 225, OR=0.68 [95% CI, 0.57-0.81]; <0.0001), hemorrhagic stroke (16 trials, n=9736, OR=0.43 [95% CI, 0.29-0.64]; =0.0001), deaths (OR=0.64 [95% CI, 0.49-0.83], <0.0009), systemic bleeding (n=8387, OR=0.73 [95% CI, 0.54-0.99]; =0.04), but increased headache and palpitations, compared with placebo, aspirin, or clopidogrel. Cilostazol reduced recurrent ischemic stroke more when given long (>6 months) versus short term without increasing hemorrhage, and in trials with larger proportions (>40%) of lacunar stroke. Data were insufficient to assess effects on cognition, imaging, functional outcomes, or tolerance.
CONCLUSIONS
Cilostazol appears effective for long-term secondary stroke prevention without increasing hemorrhage risk. However, most trials related to Asia-Pacific patients and more trials in Western countries should assess its effects on cognitive decline, functional outcome, and tolerance, particularly in lacunar stroke and other presentations of small vessel disease.
Topics: Cilostazol; Cognitive Dysfunction; Fibrinolytic Agents; Humans; Phosphodiesterase 3 Inhibitors; Secondary Prevention; Stroke
PubMed: 32646330
DOI: 10.1161/STROKEAHA.120.029454 -
Frontiers in Immunology 2022Multiple sclerosis (MS) is an inflammatory demyelinating and degenerative disease of the central nervous system (CNS). Although inflammatory responses are efficiently...
Multiple sclerosis (MS) is an inflammatory demyelinating and degenerative disease of the central nervous system (CNS). Although inflammatory responses are efficiently treated, therapies for progression are scarce and suboptimal, and biomarkers to predict the disease course are insufficient. Cure or preventive measures for MS require knowledge of core pathological events at the site of the tissue damage. Novelties in systems biology have emerged and paved the way for a more fine-grained understanding of key pathological pathways within the CNS, but they have also raised questions still without answers. Here, we systemically review the power of tissue and single-cell/nucleus CNS omics and discuss major gaps of integration into the clinical practice. Systemic search identified 49 transcriptome and 11 proteome studies of the CNS from 1997 till October 2021. Pioneering molecular discoveries indicate that MS affects the whole brain and all resident cell types. Despite inconsistency of results, studies imply increase in transcripts/proteins of semaphorins, heat shock proteins, myelin proteins, apolipoproteins and HLAs. Different lesions are characterized by distinct astrocytic and microglial polarization, altered oligodendrogenesis, and changes in specific neuronal subtypes. In all white matter lesion types, are highly expressed, and STAT6- and TGFβ-signaling are increased. In the grey matter lesions, TNF-signaling seems to drive cell death, and especially -expressing neurons may be susceptible to neurodegeneration. The vast heterogeneity at both cellular and lesional levels may underlie the clinical heterogeneity of MS, and it may be more complex than the current disease phenotyping in the clinical practice. Systems biology has not solved the mystery of MS, but it has discovered multiple molecules and networks potentially contributing to the pathogenesis. However, these results are mostly descriptive; focused functional studies of the molecular changes may open up for a better interpretation. Guidelines for acceptable quality or awareness of results from low quality data, and standardized computational and biological pipelines may help to overcome limited tissue availability and the "snap shot" problem of omics. These may help in identifying core pathological events and point in directions for focus in clinical prevention.
Topics: Brain; Humans; Multiple Sclerosis; Proteome; Transcriptome; White Matter
PubMed: 35309325
DOI: 10.3389/fimmu.2022.761225 -
Brain and Behavior Jul 2022Numerous cortical and subcortical structures have been studied extensively concerning alterations of their integrity as well as their neurotransmitters in depression.... (Review)
Review
BACKGROUND
Numerous cortical and subcortical structures have been studied extensively concerning alterations of their integrity as well as their neurotransmitters in depression. However, connections between these structures have received considerably less attention.
OBJECTIVE
This systematic review presents results from recent neuroimaging as well as neuropathologic studies conducted on humans and other mammals. It aims to provide evidence for impaired white matter integrity in individuals expressing a depressive phenotype.
METHODS
A systematic database search in accordance with the PRISMA guidelines was conducted to identify imaging and postmortem studies conducted on humans with a diagnosis of major depressive disorder, as well as on rodents and primates subjected to an animal model of depression.
RESULTS
Alterations are especially apparent in frontal gyri, as well as in structures establishing interhemispheric connectivity between frontal regions. Translational neuropathological findings point to alterations in oligodendrocyte density and morphology, as well as to alterations in the expression of genes related to myelin synthesis. An important role of early life adversities in the development of depressive symptoms and white matter alterations across species is thereby revealed. Data indicating that stress can interfere with physiological myelination patterns is presented. Altered myelination is most notably present in regions that are subject to maturation during the developmental stage of exposure to adversities.
CONCLUSION
Translational studies point to replicable alterations in white matter integrity in subjects suffering from depression across multiple species. Impaired white matter integrity is apparent in imaging as well as neuropathological studies. Future studies should focus on determining to what extent influencing white matter integrity is able to improve symptoms of depression in animals as well as humans.
Topics: Anisotropy; Brain; Depression; Depressive Disorder, Major; Diffusion Tensor Imaging; Humans; White Matter
PubMed: 35652161
DOI: 10.1002/brb3.2629 -
Bioengineering (Basel, Switzerland) Jun 2018Photobiomodulation therapy (PBMT) has been investigated because of its intimate relationship with tissue recovery processes, such as on peripheral nerve damage. Based on... (Review)
Review
Photobiomodulation therapy (PBMT) has been investigated because of its intimate relationship with tissue recovery processes, such as on peripheral nerve damage. Based on the wide range of benefits that the PBMT has shown and its clinical relevance, the aim of this research was to carry out a systematic review of the last 10 years, ascertaining the influence of the PBMT in the regeneration of injured peripheral nerves. The search was performed in the PubMed/MEDLINE database with the combination of the keywords: low-level laser therapy AND nerve regeneration. Initially, 54 articles were obtained, 26 articles of which were chosen for the study according to the inclusion criteria. In the qualitative aspect, it was observed that PBMT was able to accelerate the process of nerve regeneration, presenting an increase in the number of myelinated fibers and a better lamellar organization of myelin sheath, besides improvement of electrophysiological function, immunoreactivity, high functionality rate, decrease of inflammation, pain, and the facilitation of neural regeneration, release of growth factors, increase of vascular network and collagen. It was concluded that PBMT has beneficial effects on the recovery of nerve lesions, especially when related to a faster regeneration and functional improvement, despite the variety of parameters.
PubMed: 29890728
DOI: 10.3390/bioengineering5020044 -
Brazilian Journal of Otorhinolaryngology 2023The benefit of corticosteroids following facial nerve neurorrhaphy in the setting of complete transection is questionable. This systematic review and meta-analysis aimed... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The benefit of corticosteroids following facial nerve neurorrhaphy in the setting of complete transection is questionable. This systematic review and meta-analysis aimed to evaluate corticosteroid efficacy on facial nerve regeneration and functional recovery after complete disruption and neurorrhaphy.
METHODS
Randomized controlled trials on both human and animal models from Ovid MEDLINE and Ovid EMBASE studying corticosteroid efficacy in complete facial nerve disruption followed by neurorrhaphy were included. Data were extracted and pooled for meta-analysis. The outcomes were evaluated from electrophysiology, histology, and functional recovery. However, no randomized controlled trial in human was performed. Possibly, performing human trials with histopathology may not be feasible in clinical setting.
RESULTS
Six animal studies (248 participants) met inclusion criteria. Electrophysiologic outcomes revealed no differences in latency (Standardized Mean Difference (SMD) = -1.97, 95% CI -7.38 to 3.44, p = 0.47) and amplitude (SMD = 0.37, 95% CI -0.44 to 1.18, p = 0.37) between systemic corticosteroids and controls. When analysis compared topical corticosteroid and control, the results provided no differences in latency (Mean Difference (MD) = 0.10, 95% CI -0.04 to 0.24, p = 0.16) and amplitude (SMD = 0.01, 95% CI -0.08 to 0.10, p = 0.81). In histologic outcomes, the results showed no differences in axon diameter (MD = 0.13, 95% CI -0.15 to 0.41, p = 0.37) between systemic corticosteroid and control; however, the result in myelin thickness (MD = 0.06, 95% CI 0.04 to 0.08, p < 0.05) favored control group. When comparing systemic corticosteroid with control in eye blinking, the results favored control (MD = 1.33, 95% CI 0.60 to 2.06, p = 0.0004).
CONCLUSIONS
This evidence did not show potential benefits of systemic or topical corticosteroid deliveries after facial nerve neurorrhaphy in complete transection when evaluating electrophysiologic, histologic, and functional recovery outcomes in animal models.
Topics: Animals; Humans; Facial Nerve; Adrenal Cortex Hormones; Glucocorticoids; Models, Animal; Neurosurgical Procedures
PubMed: 34815200
DOI: 10.1016/j.bjorl.2021.09.005 -
Journal of Neurology Feb 2023Retina thickness has been studied in patients with neuromyelitis optica spectrum disorders (NMOSD) without distinguishing serostatus and limited data are available in... (Meta-Analysis)
Meta-Analysis Review
Retina thickness in clinically affected and unaffected eyes in patients with aquaporin-4 immunoglobulin G antibody seropositive neuromyelitis optica spectrum disorders: a systematic review and meta-analysis.
BACKGROUND AND PURPOSE
Retina thickness has been studied in patients with neuromyelitis optica spectrum disorders (NMOSD) without distinguishing serostatus and limited data are available in unaffected eyes. We aimed to investigate retina thickness in eyes of aquaporin-4 immunoglobulin G antibody seropositive (AQP4-IgG) NMOSD patients with optic neuritis (AQP4-ON) and without (AQP4-NON).
METHODS
Eligible studies were identified by searching PubMed and Embase. Mean difference (MD, μm) with corresponding 95% confidence interval (CI) was pooled with random-effect models. The primary measures were average thickness of peripapillar retinal nerve fiber layer (pRNFL) centered on optic disc and the combination of ganglion cell layer and inner plexiform layer (GCIPL) at macula.
RESULTS
We included 21 studies enrolling 787 AQP4-IgG NMOSD patients. Compared with healthy control, pRNFL was thinner in eyes of AQP4-ON (- 32.78, 95% CI [- 36.24, - 29.33]) and AQP4-NON (- 2.76, 95% CI [- 3.94, - 1.58]), so was GICPL in AQP4-ON (-21.38, 95% CI [- 24.01, - 18.74]) and AQP4-NON (95% CI - 2.96, [- 3.91, - 2.00]). Compared with multiple sclerosis with ON, AQP4-ON had thinner pRNFL (- 13.56, 95%CI [- 16.51, - 10.60]) and GCIPL (- 9.12, 95% CI [- 11.88, - 6.36]). AQP4-ON and myelin oligodendrocyte glycoprotein antibody-associated demyelination with ON (MOG-ON) had similar pRNFL (0.59, 95% CI [- 6.61, 7.79]) and GCIPL thickness (- 0.55, 95% CI [- 2.92, 1.82]). AQP4-NON had similar pRNFL and GCIPL thickness to MOG-NON and multiple sclerosis without ON.
CONCLUSIONS
The average thickness of pRNFL and GICPL decreased both in AQP4-ON and AQP4-NON eyes. AQP4-ON eyes had a similar level of pRNFL and GICPL thinning to MOG-ON eyes, so did AQP4-NON to MOG-NON eyes.
Topics: Humans; Neuromyelitis Optica; Immunoglobulin G; Aquaporin 4; Tomography, Optical Coherence; Retina; Optic Neuritis; Multiple Sclerosis; Autoantibodies; Myelin-Oligodendrocyte Glycoprotein
PubMed: 36355186
DOI: 10.1007/s00415-022-11482-4 -
Brain Sciences Jul 2022Myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) has been considered a diagnostic marker for patients with demyelinating disease, termed "MOG-IgG... (Review)
Review
BACKGROUND
Myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) has been considered a diagnostic marker for patients with demyelinating disease, termed "MOG-IgG associated disorder" (MOGAD). Recently, the coexistence of MOG-IgG and other neuronal or glial antibodies has attracted extensive attention from clinicians. In this article, we systematically review the characteristics of MOG-IgG-related antibody coexistence syndrome.
METHODS
Two authors independently searched PubMed for relevant studies published before October 2021. We also manually searched the references of each related article. The appropriateness of the included studies was assessed by reading the titles, abstracts, and full texts if necessary.
RESULTS
Thirty-five relevant publications that met our inclusion criteria were finally included, of which fourteen were retrospective studies and twenty-one were case reports. A total of 113 patients were reported to show the coexistence of MOG-IgG and neuronal or glial antibodies. Additionally, 68.14% of patients were double positive for MOG-IgG and N-Methyl-D-Aspartate Receptor-IgG (NMDAR-IgG), followed by 23.01% of patients who were double positive for MOG-IgG and aquaporin4-IgG (AQP4-IgG). Encephalitis was the predominant phenotype when MOG-IgG coexisted with NMDAR-IgG, probably accompanied by imaging features of demyelination. Patients with dual positivity for MOG-IgG and AQP4-IgG experienced more severe disease and more frequent relapses. The coexistence of MOG-IgG and antibodies other than NMDAR-IgG and AQP4-IgG was extremely rare, and the clinical presentations were diverse and atypical. Except for patients who were double positive for MOG-IgG and AQP4-IgG, most patients with multiple antibodies had a good prognosis.
CONCLUSIONS
MOG-IgG may coexist with neuronal or glial antibodies. Expanded screening for neuronal or glial antibodies should be performed in patients with atypical clinical and radiological features.
PubMed: 36009058
DOI: 10.3390/brainsci12080995 -
ELife Oct 2020Several MRI measures have been proposed as in vivo biomarkers of myelin, each with applications ranging from plasticity to pathology. Despite the availability of these... (Meta-Analysis)
Meta-Analysis
Several MRI measures have been proposed as in vivo biomarkers of myelin, each with applications ranging from plasticity to pathology. Despite the availability of these myelin-sensitive modalities, specificity and sensitivity have been a matter of discussion. Debate about which MRI measure is the most suitable for quantifying myelin is still ongoing. In this study, we performed a systematic review of published quantitative validation studies to clarify how different these measures are when compared to the underlying histology. We analyzed the results from 43 studies applying meta-analysis tools, controlling for study sample size and using interactive visualization (https://neurolibre.github.io/myelin-meta-analysis). We report the overall estimates and the prediction intervals for the coefficient of determination and find that MT and relaxometry-based measures exhibit the highest correlations with myelin content. We also show which measures are, and which measures are not statistically different regarding their relationship with histology.
Topics: Animals; Biomarkers; Humans; Magnetic Resonance Imaging; Mice; Myelin Sheath; Rats
PubMed: 33084576
DOI: 10.7554/eLife.61523 -
International Journal of Molecular... Feb 2024A spinal cord injury (SCI) causes changes in brain structure and brain function due to the direct effects of nerve damage, secondary mechanisms, and long-term effects of... (Review)
Review
A spinal cord injury (SCI) causes changes in brain structure and brain function due to the direct effects of nerve damage, secondary mechanisms, and long-term effects of the injury, such as paralysis and neuropathic pain (NP). Recovery takes place over weeks to months, which is a time frame well beyond the duration of spinal shock and is the phase in which the spinal cord remains unstimulated below the level of injury and is associated with adaptations occurring throughout the nervous system, often referred to as neuronal plasticity. Such changes occur at different anatomical sites and also at different physiological and molecular biological levels. This review aims to investigate brain plasticity in patients with SCIs and its influence on the rehabilitation process. Studies were identified from an online search of the PubMed, Web of Science, and Scopus databases. Studies published between 2013 and 2023 were selected. This review has been registered on OSF under (n) 9QP45. We found that neuroplasticity can affect the sensory-motor network, and different protocols or rehabilitation interventions can activate this process in different ways. Exercise rehabilitation training in humans with SCIs can elicit white matter plasticity in the form of increased myelin water content. This review has demonstrated that SCI patients may experience plastic changes either spontaneously or as a result of specific neurorehabilitation training, which may lead to positive outcomes in functional recovery. Clinical and experimental evidence convincingly displays that plasticity occurs in the adult CNS through a variety of events following traumatic or non-traumatic SCI. Furthermore, efficacy-based, pharmacological, and genetic approaches, alone or in combination, are increasingly effective in promoting plasticity.
Topics: Humans; Spinal Cord Injuries; Spinal Cord; Brain; Neuronal Plasticity; Recovery of Function
PubMed: 38396902
DOI: 10.3390/ijms25042224 -
Current Genomics Nov 2018Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests... (Review)
Review
Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.
PubMed: 30386171
DOI: 10.2174/1389202919666171229145156