Experimental Models to Study Immune Dysfunction in the Pathogenesis of Parkinson's Disease.

Parkinson's disease (PD) is a chronic, age-related, progressive multisystem disease associated with neuroinflammation and immune dysfunction. This review discusses the methodological approaches used to study the changes in central and peripheral immunity in PD, the advantages and limitations of the techniques, and their applicability to humans. Although a single animal model cannot replicate all pathological features of the human disease, neuroinflammation is present in most animal models of PD and plays a critical role in understanding the involvement of the immune system (IS) in the pathogenesis of PD. The IS and its interactions with different cell types in the central nervous system (CNS) play an important role in the pathogenesis of PD. Even though culture models do not fully reflect the complexity of disease progression, they are limited in their ability to mimic long-term effects and need validation through in vivo studies. They are an indispensable tool for understanding the interplay between the IS and the pathogenesis of this disease. Understanding the immune-mediated mechanisms may lead to potential therapeutic targets for the treatment of PD. We believe that the development of methodological guidelines for experiments with animal models and PD patients is crucial to ensure the validity and consistency of the results.

Hyperglycemia with or without insulin resistance triggers different structural changes in brain microcirculation and perivascular matrix.

Both type-1 and type-2 DM are related to an increased risk of cognitive impairment, neurovascular complications, and dementia. The primary triggers for complications are hyperglycemia and concomitant insulin resistance in type-2 DM. However, the diverse mechanisms in the pathogenesis of diabetes-related neurovascular complications and extracellular matrix (ECM) remodeling in type-1 and 2 have not been elucidated yet. Here, we investigated the high fat-high sucrose (HFHS) feeding model and streptozotocin-induced type-1 DM model to study the early effects of hyperglycemia with or without insulin resistance to demonstrate the brain microcirculatory changes, perivascular ECM alterations in histological sections and 3D-reconstructed cleared brain tissues. One of the main findings of this study was robust rarefaction in brain microvessels in both models. Interestingly, the HFHS model leads to widespread non-functional angiogenesis, but the type-1 DM model predominantly in the rostral brain. Rarefaction was accompanied by basement membrane thickening and perivascular collagen accumulation in type-1 DM; more severe blood-brain barrier leakage, and disruption of perivascular ECM organization, mainly of elastin and collagen fibers' structural integrity in the HFHS model. Our results point out that the downstream mechanisms of the long-term vascular complications of hyperglycemia models are structurally distinctive and may have implications for appropriate treatment options.

The role of extracellular matrix alterations in mediating astrocyte damage and pericyte dysfunction in Alzheimer's disease: A comprehensive review.

The brain is a highly vascularized tissue protected by the blood-brain barrier (BBB), a complex structure allowing only necessary substances to pass through into the brain while limiting the entrance of harmful toxins. The BBB comprises several components, and the most prominent features are tight junctions between endothelial cells (ECs), which are further wrapped in a layer of pericytes. Pericytes are multitasked cells embedded in a thick basement membrane (BM) that consists of a fibrous extracellular matrix (ECM) and are surrounded by astrocytic endfeet. The primary function of astrocytes and pericytes is to provide essential blood supply and vital nutrients to the brain. In Alzheimer's disease (AD), long-term neuroinflammatory cascades associated with infiltration of harmful neurotoxic proteins may lead to BBB dysfunction and altered ECM components resulting in brain homeostatic imbalance, synaptic damage, and declined cognitive functions. Moreover, BBB structure and functional integrity may be lost due to induced ECM alterations, astrocyte damage, and pericytes dysfunction, leading to amyloid-beta (Aß) hallmarks deposition in different brain regions. Herein, we highlight how BBB, ECM, astrocytes, and pericytes dysfunction can play a leading role in AD's pathogenesis and discuss their impact on brain functions.

Hand Pronation-Supination Movement as a Proxy for Remotely Monitoring Gait and Posture Stability in Parkinson's Disease.

The Unified Parkinson's Disease Rating Scale (UPDRS) is a subjective Parkinson's Disease (PD) physician scoring/monitoring system. To date, there is no single upper limb wearable/non-contact system that can be used objectively to assess all UPDRS-III motor system subgroups (i.e., tremor (T), rigidity (R), bradykinesia (B), gait and posture (GP), and bulbar anomalies (BA)). We evaluated the use of a non-contact hand motion tracking system for potential extraction of GP information using forearm pronation-supination (P/S) motion parameters (speed, acceleration, and frequency). Twenty-four patients with idiopathic PD participated, and their UPDRS data were recorded bilaterally by physicians. Pearson's correlation, regression analyses, and Monte Carlo validation was conducted for all combinations of UPDRS subgroups versus motion parameters. In the 262,125 regression models that were trained and tested, the models within 1% of the lowest error showed that the frequency of P/S contributes to approximately one third of all models; while speed and acceleration also contribute significantly to the prediction of GP from the left-hand motion of right handed patients. In short, the P/S better indicated GP when performed with the non-dominant hand. There was also a significant negative correlation (with medium to large effect size, range: 0.3-0.58) between the P/S speed and the single BA score for both forearms and combined UPDRS score for the dominant hand. This study highlights the potential use of wearable or non-contact systems for forearm P/S to remotely monitor and predict the GP information in PD.

Cortical spreading depression can be triggered by sensory stimulation in primed wild type mouse brain: a mechanistic insight to migraine aura generation.

BACKGROUND: Unlike the spontaneously appearing aura in migraineurs, experimentally, cortical spreading depression (CSD), the neurophysiological correlate of aura is induced by non-physiological stimuli. Consequently, neural mechanisms involved in spontaneous CSD generation, which may provide insight into how migraine starts in an otherwise healthy brain, remain largely unclear. We hypothesized that CSD can be physiologically induced by sensory stimulation in primed mouse brain. METHODS: Cortex was made susceptible to CSD with partial inhibition of Na+/K+-ATPase by epidural application of a low concentration of Na+/K+-ATPase blocker ouabain, allowing longer than 30-min intervals between CSDs or by knocking-down α2 subunit of Na+/K+-ATPase, which is crucial for K+ and glutamate re-uptake, with shRNA. Stimulation-triggered CSDs and extracellular K+ changes were monitored in vivo electrophysiologically and a K+-sensitive fluoroprobe (IPG-4), respectively. RESULTS: After priming with ouabain, photic stimulation significantly increased the CSD incidence compared with non-stimulated animals (44.0 vs. 4.9%, p < 0.001). Whisker stimulation also significantly increased the CSD incidence, albeit less effectively (14.9 vs. 2.4%, p = 0.02). Knocking-down Na+/K+-ATPase (50% decrease in mRNA) lowered the CSD threshold in all mice tested with KCl but triggered CSDs in 14.3% and 16.7% of mice with photic and whisker stimulation, respectively. Confirming Na+/K+-ATPase hypofunction, extracellular K+ significantly rose during sensory stimulation after ouabain or shRNA treatment unlike controls. In line with the higher CSD susceptibility observed, K+ rise was more prominent after ouabain. To gain insight to preventive mechanisms reducing the probability of stimulus-evoked CSDs, we applied an A1-receptor antagonist (DPCPX) to the occipital cortex, because adenosine formed during stimulation from ATP can reduce CSD susceptibility. DPCPX induced spontaneous CSDs but only small-DC shifts along with suppression of EEG spikes during photic stimulation, suggesting that the inhibition co-activated with sensory stimulation could limit CSD ignition when K+ uptake was not sufficiently suppressed as with ouabain. CONCLUSIONS: Normal brain is well protected against CSD generation. For CSD to be ignited under physiological conditions, priming and predisposing factors are required as seen in migraine patients. Intense sensory stimulation has potential to trigger CSD when co-existing conditions bring extracellular K+ and glutamate concentrations over CSD-ignition threshold and stimulation-evoked inhibitory mechanisms are overcome.

Three-dimensional neuron-astrocyte construction on matrigel enhances establishment of functional voltage-gated sodium channels.

This study aimed to investigate and compare cell growth manners and functional differences of primary cortical neurons cultured on either poly-d-lysine (PDL) and or Matrigel, to delineate the role of extracellular matrix on providing resemblance to in vivo cellular interactions in nervous tissue. Primary cortical neurons, obtained from embryonic day 15 mice pups, seeded either on PDL- or Matrigel-coated culture ware were investigated by DIC/bright field and fluorescence/confocal microscopy for their morphology, 2D and 3D structure, and distribution patterns. Patch clamp, western blot, and RT-PCR studies were performed to investigate neuronal firing thresholds and sodium channel subtypes Nav1.2 and Nav1.6 expression. Cortical neurons cultured on PDL coating possessed a 2D structure composed of a few numbers of branched and tortuous neurites that contacted with each other in one to one manner, however, neurons on Matrigel coating showed a more complicated dimensional network that depicted tight, linear axonal bundles forming a 3D interacted neuron-astrocyte construction. This difference in growth patterns also showed a significant alteration in neuronal firing threshold which was recorded between 80 < Iinj > 120 pA on PDL and 2 < Iinj > 160 pA on Matrigel. Neurons grown up on Matrigel showed increased levels of sodium channel protein expression of Nav1.2 and Nav1.6 compared to neurons on PDL. These results have demonstrated that a 3D interacted neuron-astrocyte construction on Matrigel enhances the development of Nav1.2 and Nav1.6 in vitro and decreases neuronal firing threshold by 40 times compared to conventional PDL, resembling in vivo neuronal networks and hence would be a better in vitro model of adult neurons.

Occipital bending in migraine with visual aura.

OBJECTIVE: To analyze occipital bending (OB) frequency in patients with migraine with visual aura compared with those without aura. BACKGROUND: A unique type of asymmetry in the human brain in which one occipital pole crosses the midline and bends over the other pole is called OB. OB frequency has been shown to be related to major psychiatric diseases. Hence, it may suggest more than an anatomical variation. Structural differences in the brain have been demonstrated but unequivocally between patients with migraine with aura and without aura. OB is newly recognized, and we aimed to evaluate its frequency among patients with migraine. METHODS: For this retrospective cohort study, we reviewed our records from 2016 to 2021 from a database of the outpatient headache clinic of Koç University Hospital. RESULTS: We found 84 patients with migraine who fulfilled diagnostic criteria for migraine with aura and migraine without aura and also had cranial magnetic resonance imaging. The median age of the population was 40 (IQR, 32-52). The female-to-male ratio of participants was 2:1. A quarter of the patients had visual aura. The prevalence of OB in patients with migraine in our retrospective study was 33.3% (28/84). Between our study groups, OB was significantly higher in patients with migraine with visual aura (57.1%, 12 out of 21 patients) than in those without aura (25.4%, 16 out of 63), (odds ratio 3.9 (95% confidence interval 1.4 to 11.0), p = 0.015). CONCLUSION: OB frequency is two times higher in patients with migraine with visual aura. It may have pathophysiological implications.

Blood-brain barrier leakage and perivascular collagen accumulation precede microvessel rarefaction and memory impairment in a chronic hypertension animal model.

Hypertension (HT) is one of the main causes of vascular dementia, lead to cognitive decline. Here, we investigated the relationship between cerebral microvessels, pericytes, extracellular matrix (ECM) accumulation, blood-brain barrier (BBB) breakdown, and memory impairment at mid-life in a chronic hypertension animal model. Spontaneously hypertensive rats (SHRs) (n = 20) are chosen for the model and age matched Wistar rats (n = 16) as controls. Changes in brain microvasculature and in vitro experiments are shown with immunofluorescence studies and cognition with open field, novel object recognition, and Y maze tests. There was a significant reduction in pericyte coverage in SHRs (p = 0.021), while the quantitative parameters of the cerebral microvascular network were not different between groups. On the other hand, parenchymal albumin leakage, as a Blood-brain barrier (BBB) breakdown marker, was prominent in SHRs (p = 0.023). Extracellular matrix (ECM) components, collagen type 1, 3 and 4 were significantly increased (accumulated) around microvasculature in SHRs (p = 0.011, p = 0.013, p = 0.037, respectively). Furthermore, in vitro experiments demonstrated that human brain vascular pericytes but not astrocytes and endothelial cells secreted type I collagen upon TGFß1 exposure pointing out a possible role of pericytes in increased collagen accumulation around cerebral microvasculature due to HT. Furthermore, valsartan treatment decreased the amount of collagen type 1 secreted by pericytes after TGFß1 exposure. At the time of evaluation, SHRs did not demonstrate cognitive decline and memory impairments. Our results showed that chronic HT causes ECM accumulation and BBB leakage before leading to memory impairments and therefore, pericytes could be a novel target for preventing vascular dementia.

Inadequate brain glycogen or sleep increases spreading depression susceptibility.

OBJECTIVE: Glycogen in astrocyte processes contributes to maintenance of low extracellular glutamate and K+ concentrations around excitatory synapses. Sleep deprivation (SD), a common migraine trigger, induces transcriptional changes in astrocytes, reducing glycogen breakdown. We hypothesize that when glycogen utilization cannot match synaptic energy demand, extracellular K+ can rise to levels that activate neuronal pannexin-1 channels and downstream inflammatory pathway, which might be one of the mechanisms initiating migraine headaches. METHODS: We suppressed glycogen breakdown by inhibiting glycogen phosphorylation with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and by SD. RESULTS: DAB caused neuronal pannexin-1 large pore opening and activation of the downstream inflammatory pathway as shown by procaspase-1 cleavage and HMGB1 release from neurons. Six-hour SD induced pannexin-1 mRNA. DAB and SD also lowered the cortical spreading depression (CSD) induction threshold, which was reversed by glucose or lactate supplement, suggesting that glycogen-derived energy substrates are needed to prevent CSD generation. Supporting this, knocking down the neuronal lactate transporter MCT2 with an antisense oligonucleotide or inhibiting glucose transport from vessels to astrocytes with intracerebroventricularly delivered phloretin reduced the CSD threshold. In vivo recordings with a K+ -sensitive/selective fluoroprobe, Asante Potassium Green-4, revealed that DAB treatment or SD caused a significant rise in extracellular K+ during whisker stimulation, illustrating the critical role of glycogen in extracellular K+ clearance. INTERPRETATION: Synaptic metabolic stress caused by insufficient glycogen-derived energy substrate supply can activate neuronal pannexin-1 channels as well as lower the CSD threshold. Therefore, conditions that limit energy supply to synapses (eg, SD) may predispose to migraine attacks, as suggested by genetic studies associating glucose or lactate transporter deficiency with migraine. Ann Neurol 2018;83:61-73.

Isolated hypoglossal nerve palsy due to a jugular foramen schwannoma.

Introduction - Although the involvement of the hypoglossal nerve together with other cranial nerves is common in several pathological conditions of the brain, particularly the brainstem, isolated hypoglossal nerve palsy is a rare condition and a diagnostic challenge. Case presentation - The presented patient arrived to the hospital with a history of slurred speech and an uncomfortable sensation on his tongue. Neurological examination showed left-sided hemiatrophy of the tongue with fasciculations and deviation towards the left side during protrusion. Based on the clinical and MRI findings, a diagnosis of hypoglossal nerve schwannoma was made. Discussion - Hypoglossal nerve palsy may arise from multiple causes such as trauma, infections, neoplasms, and endocrine, autoimmune and vascular pathologies. In our case, the isolated involvement of the hypoglossal nerve was at the skull base segment, where the damage to the hypoglossal nerve may occur mostly due to metastasis, nasopharyngeal carcinomas, nerve sheath tumors and glomus tumors. Conclusion - Because of the complexity of the region's anatomy, the patient diagnosed with hypoglossal nerve schwannoma was referred for gamma knife radiosurgery.

Improving Microcirculatory Reperfusion Reduces Parenchymal Oxygen Radical Formation and Provides Neuroprotection.

BACKGROUND AND PURPOSE: Reperfusion is the most significant determinant of good outcome after ischemic stroke. However, complete reperfusion often cannot be achieved, despite satisfactory recanalization. We hypothesized that microvascular protection was essential for achieving effective reperfusion and, hence, neuroprotection. To test this hypothesis, we have developed an in vivo model to differentially monitor parenchymal and vascular reactive oxygen species (ROS) formation. By comparing the ROS-suppressing effect of N-tert-butyl-α-phenylnitrone (PBN) with its blood-brain barrier impermeable analog 2-sulfo-phenyl-N-tert-butylnitrone (S-PBN), we assessed the impact of vascular ROS suppression alone on reperfusion and stroke outcome after recanalization. METHODS: The distal middle cerebral artery was occluded for 1 hour by compressing with a micropipette and then recanalized (n=60 Swiss mice). ROS formation was monitored for 1 hour after recanalization by intravital fluorescence microscopy in pial vasculature and cortical parenchyma with topically applied hydroethidine through a cranial window. PBN (100 mg/kg) or S-PBN (156 mg/kg) was administered shortly before recanalization, and suppression of the vascular and parenchymal hydroethidine fluorescence was examined (n=22). Microcirculatory patency, reperfusion, ischemic tissue size, and neurological outcome were also assessed in a separate group of mice 1 to 72 hours after recanalization (n=30). RESULTS: PBN and S-PBN completely suppressed the reperfusion-induced increase in ROS signal within vasculature. PBN readily suppressed ROS produced in parenchyma by 88%. S-PBN also suppressed the parenchymal ROS by 64% but starting 40 minutes later. Intriguingly, PBN and S-PBN comparably reduced the size of ischemic area by 65% and 48% (P>0.05), respectively. S-PBN restored the microvascular patency and perfusion after recanalization, suggesting that its delayed parenchymal antioxidant effect could be secondary to improved microcirculatory reperfusion. CONCLUSIONS: Promoting microvascular reperfusion by protecting vasculature can secondarily reduce parenchymal ROS formation and provide neuroprotection. The model presented can be used to directly assess pharmacological end points postulated in brain parenchyma and vasculature in vivo.

Optical coherence tomography imaging of capillary reperfusion after ischemic stroke.

Although progress has been made for recanalization therapies after ischemic stroke, post-treatment imaging studies show that tissue reperfusion cannot be attained despite satisfactory recanalization in a significant percentage of patients. Hence, investigation of microcirculatory changes in both surface and deep cortical levels after ischemia reperfusion is important for understanding the post-stroke blood flow dynamics. In this study, we applied optical coherence tomography (OCT) imaging of cerebral blood flow for the quantification of the microcirculatory changes. We obtained OCT microangiogram of the brain cortex in a mouse stroke model and analyzed the data to trace changes in the capillary perfusion level (CPL) before, during, and after the stroke. The CPL changes were estimated in 1 and 2 h ischemia groups as well as in a non-ischemic sham-operated group. For the estimation of CPL, a decorrelation amplitude-based algorithm was implemented and used. As a result, the CPL considerably decreased during ischemia but recovered to the baseline when recanalization was performed 1 h after ischemia; however, the CPL was significantly reduced when recanalization was delayed to 2 h after ischemia. These data demonstrate that ischemia causes microcirculation dysfunction, leading to a decreased capillary reperfusion after recanalization. Microcirculatory no-reflow warrants more rigorous assessment in clinical trials, whereas advanced optical imaging techniques may provide mechanistic insight and solutions in experimental studies.

Poloxamer-188 and citicoline provide neuronal membrane integrity and protect membrane stability in cortical spreading depression.

Under pathological conditions such as brain trauma, subarachnoid hemorrhage and stroke, cortical spreading depression (CSD) or peri-infarct depolarizations contribute to brain damage in animal models of neurological disorders as well as in human neurological diseases. CSD causes transient megachannel opening on the neuronal membrane, which may compromise neuronal survival under pathological conditions. Poloxamer-188 (P-188) and citicoline are neuroprotectants with membrane sealing properties. The aim of this study is to investigate the effect of P-188 and citicoline on the neuronal megachannel opening induced by CSD in the mouse brain. We have monitored megachannel opening with propidium iodide, a membrane impermeable fluorescent dye and, demonstrate that P-188 and citicoline strikingly decreased CSD-induced neuronal PI influx in cortex and hippocampal dentate gyrus. Therefore, these agents may be providing neuroprotection by blocking megachannel opening, which may be related to their membrane sealing action and warrant further investigation for treatment of traumatic brain injury and ischemic stroke.

Atypical Aicardi-Goutieres syndrome: is the WRN locus a modifier?

We describe a 28-year-old Turkish man with consanguineous parents who presented with an aged appearance with prematurely gray hair and scleroderma-like skin, spastic paraplegia, and apparent disability. The proband and each of his parents were heterozygous for a mutation in WRN, which could not explain his symptoms. Exome sequencing of the proband's blood DNA showed a homozygous c.626-1G > C mutation in intron 5 of the SAMHD1 gene, which encodes a triphosphohydrolase involved in the regulation of intracellular dNTP pools and which is mutated in Aicardi-Goutieres syndrome. The RNA studies confirmed aberrant splicing of exon 6, and family studies showed that both parents are heterozygous for this mutation. We conclude that mutations in SAMHD1 - in addition to causing an early-onset form of encephalopathy in Aicardi-Goutieres syndrome - may present with modest signs of accelerated aging similar to Werner syndrome. The extent to which heterozygosity at the WRN locus may modify the effect of biallelic SAMHD1 mutations is unknown. It is conceivable that synergistic effects of these two mutations might be responsible for the unusual phenotype.

Carbenoxolone mitigates extensive fibrosis formation in PLP-induced EAE model and multiple sclerosis serum-exposed pericyte culture.

Introduction: Multiple sclerosis (MS) is one of the most common causes of disability in young adults. Nearly, 85% of MS cases start with attacks and remissions, classified as relapsing-remitting multiple sclerosis (RRMS). With repeating attacks, MS causes brain-spinal cord atrophy and enhanced disability as disease progresses. PLP-induced EAE is one of the most established models for pathophysiology and treatment of RRMS. Recent studies demonstrated the possible role of pericytes in perivascular and intra-lesional fibrosis in PLP-induced EAE, whose importance remains elusive. Hence, we have investigated the possible role of pericytes in fibrosis formation and amelioration with a hemichannel blocker, Carbenoxolone (CBX). Methods: PLP-induced experimental autoimmune encephalitis (EAE) model is used and the effect of CBX is investigated. Clinical scores were recorded and followed. Perivascular Collagen 1 and 3 accumulations were demonstrated as markers of fibrosis in the spinal cord. To delineate the role of pericytes, human brain vascular pericytes (HBVP) were incubated with the sera of MS patients to induce in-vitro MS model and the fibrosis formation was investigated. Results: In the PLP induced in-vivo model, both intracerebroventricular and intraperitoneal CBX have significantly mitigated the disease progression followed by clinical scores, demyelination, and fibrosis. Moreover, CBX significantly mitigated MS-serum-induced fibrosis in the HBVP cell culture. Discussion: The study demonstrated two important findings. First, CBX decreases fibrosis formation in both in-vivo and in-vitro MS models. Secondly, it improves neurological scores and decreases demyelination in the EAE model. Therefore, CBX can be potential novel therapeutic option in treating Multiple Sclerosis.

Exosomes encapsulated in hydrogels for effective central nervous system drug delivery.

The targeted delivery of pharmacologically active molecules, metabolites, and growth factors to the brain parenchyma has become one of the major challenges following the onset of neurodegeneration and pathological conditions. The therapeutic effect of active biomolecules is significantly impaired after systemic administration in the central nervous system (CNS) because of the blood-brain barrier (BBB). Therefore, the development of novel therapeutic approaches capable of overcoming these limitations is under discussion. Exosomes (Exo) are nano-sized vesicles of endosomal origin that have a high distribution rate in biofluids. Recent advances have introduced Exo as naturally suitable bio-shuttles for the delivery of neurotrophic factors to the brain parenchyma. In recent years, many researchers have attempted to regulate the delivery of Exo to target sites while reducing their removal from circulation. The encapsulation of Exo in natural and synthetic hydrogels offers a valuable strategy to address the limitations of Exo, maintaining their integrity and controlling their release at a desired site. Herein, we highlight the current and novel approaches related to the application of hydrogels for the encapsulation of Exo in the field of CNS tissue engineering.

Individual-based predominance of visual input in multisensorial integration for balance is correlated with proprioceptive drift in rubber hand illusion.

Rubber hand illusion (RHI) is a traditional task that examines multisensory integration. The visual capture of tactile stimulus given to the seen rubber hand was considered to predominate the sensory processing and interfere with the bottom-up proprioceptive and tactile inputs received from the unseen real hand that results in mislocalization of participants hand towards rubber hand, namely proprioceptive drift (PD). Another task that requires multisensorial integration and shows a predominance of visual input is the maintenance of body posture. However, if the predominance of visual input in one task is generalizable to another task is yet to be elucidated. We aimed to examine if individual dependency on visual inputs in multisensorial integration in balance correlated with PD in RHI. Twenty healthy participants were recruited for the study and completed the RHI task. The contribution of visual inputs to the static body balance was measured with the instrumented clinical test of sensory interaction for balance and indexed with Romberg Quotient (RQ). We found a moderate positive correlation between PD and RQ. Individuals with more dependence on visual information in maintaining body posture had higher PD in RHI. Our results indicate that there can be an individual-based dependence on particular domains of sensory input preserved during different tasks of multisensorial integration. Future studies must clarify whether this tendency relates to certain physical or physiological traits.

Chloride intracellular channel protein-1 (CLIC1) antibody in multiple sclerosis patients with predominant optic nerve and spinal cord involvement.

INTRODUCTION: Antibodies to cell surface proteins of astrocytes have been described in chronic inflammatory demyelinating disorders (CIDD) of the central nervous system including multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Our aim was to identify novel anti-astrocyte autoantibodies in relapsing remitting MS (RRMS) patients presenting predominantly with spinal cord and optic nerve attacks (MS-SCON). METHODS: Sera of 29 MS-SCON patients and 36 healthy controls were screened with indirect immunofluorescence to identify IgG reacting with human astrocyte cultures. Putative target autoantigens were investigated with immunoprecipitation (IP) and liquid chromatography-mass/mass spectrometry (LC-MS/MS) studies using cultured human astrocytes. Validation of LC-MS/MS results was carried out by IP and ELISA. RESULTS: Antibodies to astrocytic cell surface antigens were detected in 5 MS-SCON patients by immunocytochemistry. LC-MS/MS analysis identified chloride intracellular channel protein-1 (CLIC1) as the single common membrane antigen in 2 patients with MS-SCON. IP experiments performed with the commercial CLIC1 antibody confirmed CLIC1-antibody. Home made ELISA using recombinant CLIC1 protein as the target antigen identified CLIC1 antibodies in 9/29 MS-SCON and 3/15 relapsing inflammatory optic neuritis (RION) patients but in none of the 30 NMOSD patients, 36 RRMS patients with only one or no myelitis/optic neuritis attacks and 36 healthy controls. Patients with CLIC1-antibodies showed trends towards exhibiting reduced disability scores. CONCLUSION: CLIC1-antibody was identified for the first time in MS and RION patients, confirming once again anti-astrocytic autoimmunity in CIDD. CLIC1-antibody may potentially be utilized as a diagnostic biomarker for differentiation of MS from NMOSD.

Perivascular PDGFRB+ cells accompany lesion formation and clinical evolution differentially in two different EAE models.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that may lead to progressive disability. Here, we explored the behavioral pattern and the role of vasculature especially PDGFRB+ pericytes/ perivascular cells, in MS pathogenesis. METHODS: We have evaluated vascular changes in two different experimental allergic encephalomyelitis (EAE) mice models (MOG and PLP-induced). PDGFRB+ cells demonstrated distinct and different behavioral patterns. In both models, fibrosis formation was detected via collagen, fibronectin, and extracellular matrix accumulation. RESULTS: The PLP-induced animal model revealed that fibrosis predominantly occurs in perivascular locations and that PDGFRB+ cells are accumulated around vessels. Also, the expression of fibrotic genes and genes coding extracellular matrix (ECM) proteins are upregulated. Moreover, the perivascular thick wall structures in affected vessels of this model presented primarily increased PDGFRB+ cells but not NG2+ cells in the transgenic NG2-DsRed transgenic animal model. On the other hand, in MOG induced model, PDGFRB+ perivascular cells were accumulated at the lesion sites. PDGFRB+ cells colocalized with ECM proteins (collagen, fibronectin, and lysyl oxidase L3). Nevertheless, both MOG and PLP-immunized mice showed increasing EAE severity, and disability parallel with enhanced perivascular cell accumulation as the disease progressed from earlier (day 15) to later (day 40). CONCLUSION: As a result, we have concluded that PDGFRB+ perivascular cells may be participating in lesion progression and as well as demonstrating different responses in different EAE models.

Microvascular protection is essential for successful neuroprotection in stroke.

Currently, the best way of neuroprotection for acute ischemic stroke appears to be restoration of blood flow to the ischemic area by thrombolysis. Unfortunately, a short therapeutic time window as well as thrombolysis-induced bleeding and edema limit the use of recanalization therapies. Here, we review the evidence suggesting that ischemia/reperfusion-induced microvascular injury plays a critical role in determining tissue survival after recanalization in focal cerebral ischemia by disrupting the blood-brain barrier integrity and promoting microcirculatory clogging. Among many complex mechanisms of the ischemia-reperfusion injury, overproduction of oxygen and nitrogen radicals on the microvascular wall appears to significantly contribute to these pathological processes. These developments bring about the exciting possibility that effective suppression of oxidative/nitrative stress during pharmacological or interventional re-opening of the occluded artery may significantly improve the outcome of recanalization therapies in stroke patients by improving microcirculatory reflow as well as by preventing hemorrhagic conversion and vasogenic edema. They also point to the critical (but partly neglected) importance of the microcirculation in neuroprotection.