Deep Proteome Analysis of Cerebrospinal Fluid from Pediatric Patients with Central Nervous System Cancer.

The cerebrospinal fluid (CSF) is a key matrix for discovery of biomarkers relevant for prognosis and the development of therapeutic targets in pediatric central nervous system malignancies. However, the wide range of protein concentrations and age-related differences in children makes such discoveries challenging. In addition, pediatric CSF samples are often sparse and first prioritized for clinical purposes. The present work focused on optimizing each step of the proteome analysis workflow to extract the most detailed proteome information possible from the limited CSF resources available for research purposes. The strategy included applying sequential ultracentrifugation to enrich for extracellular vesicles (EV) in addition to analysis of a small volume of raw CSF, which allowed quantification of 1351 proteins (+55% relative to raw CSF) from 400 µL CSF. When including a spectral library, a total of 2103 proteins (+240%) could be quantified. The workflow was optimized for CSF input volume, tryptic digestion method, gradient length, mass spectrometry data acquisition method and database search strategy to quantify as many proteins a possible. The fully optimized workflow included protein aggregation capture (PAC) digestion, paired with data-independent acquisition (DIA, 21 min gradient) and allowed 2989 unique proteins to be quantified from only 400 µL CSF, which is a 340% increase in proteins compared to analysis of a tryptic digest of raw CSF.

Effect of hypoxia on BOLD fMRI response and total cerebral blood flow in migraine with aura patients.

Experimentally induced hypoxia triggers migraine and aura attacks in patients suffering from migraine with aura (MA). We investigated the blood oxygenation level-dependent (BOLD) signal response to visual stimulation during hypoxia in MA patients and healthy volunteers. In a randomized double-blind crossover study design, 15 MA patients were allocated to 180 min of normobaric poikilocapnic hypoxia (capillary oxygen saturation 70-75%) or sham (normoxia) on two separate days and 14 healthy volunteers were exposed to hypoxia. The BOLD functional MRI (fMRI) signal response to visual stimulation was measured in the visual cortex ROIs V1-V5. Total cerebral blood flow (CBF) was calculated by measuring the blood velocity in the internal carotid arteries and the basilar artery using phase-contrast mapping (PCM) MRI. Hypoxia induced a greater decrease in BOLD response to visual stimulation in V1-V4 in MA patients compared to controls. There was no group difference in hypoxia-induced total CBF increase. In conclusion, the study demonstrated a greater hypoxia-induced decrease in BOLD response to visual stimulation in MA patients. We suggest this may represent a hypoxia-induced change in neuronal excitability or abnormal vascular response to visual stimulation, which may explain the increased sensibility to hypoxia in these patients leading to migraine attacks.

Optical coherence tomography in multiple sclerosis.

To summarize recent findings regarding the utility of optical coherence tomography in multiple sclerosis. We searched PubMed for relevant articles using the keywords 'optical coherence tomography multiple sclerosis'. Additional articles were found via references in these articles. We selected articles based on relevance. Optical coherence tomography has contributed to greater insights into the pathophysiology of multiple sclerosis. Loss of retinal nerve fibre layer and ganglion cell layer thickness correlate with clinical and paraclinical parameters such as visual function, disability and magnetic resonance imaging. Some studies indicate that OCT parameters may be able to predict disability progression and visual function in MS. OCT angiography has recently emerged as a novel technique to study MS. OCT has proven very useful with regards to research, monitoring and predicting disability in multiple sclerosis. It will be interesting to see how OCT angiography will contribute to this field.

Carbon monoxide inhalation induces headache in a human headache model.

Introduction Carbon monoxide (CO) is an endogenously produced signalling molecule that has a role in nociceptive processing and cerebral vasodilatation. We hypothesized that inhalation of CO would induce headache and vasodilation of cephalic and extracephalic arteries. Methods In a randomized, double-blind, placebo-controlled crossover design, 12 healthy volunteers were allocated to inhalation of CO (carboxyhemoglobin 22%) or placebo on two separate days. Headache was scored on a verbal rating scale from 0-10. We recorded mean blood velocity in the middle cerebral artery (VMCA) by transcranial Doppler, diameter of the superficial temporal artery (STA) and radial artery (RA) by high-resolution ultrasonography and facial skin blood flow by laser speckle contrast imaging. Results Ten volunteers developed headache after CO compared to six after placebo. The area under the curve for headache (0-12 hours) was increased after CO compared with placebo ( p = 0.021). CO increased VMCA ( p = 0.002) and facial skin blood flow ( p = 0.012), but did not change the diameter of the STA ( p = 0.060) and RA ( p = 0.433). Conclusion In conclusion, the study demonstrated that CO caused mild prolonged headache but no arterial dilatation in healthy volunteers. We suggest this may be caused by a combination of hypoxic and direct cellular effects of CO.

Retinal ganglion cell analysis in multiple sclerosis and optic neuritis: a systematic review and meta-analysis.

The aim of this study was to summarise existing findings regarding optical coherence tomography (OCT) measurements of ganglion cell layer (GCL) alterations in optic neuritis (ON) and multiple sclerosis (MS). Peer-reviewed studies published prior to April 2016 were searched using PubMed, EMBASE, Web of Science and Scopus. Studies were included if they measured GCL thickness using OCT in patients with either ON, MS or clinically isolated syndrome. For the meta-analysis, we compared GCL thickness in MS patients with and without prior ON, to healthy controls. 42/252 studies were reviewed. In acute ON, studies showed significant thinning of the GCL within the first 5 weeks (n = 5), earlier than retinal nerve fibre layer (RNFL) thinning. GCL thinning at 1-2 months after acute ON predicted visual function at 6 months (n = 3). The meta-analysis showed that the thickness of the GCL was significantly reduced in MS patients both with and without previous ON compared to healthy controls. GCL thinning was associated with visual function in most studies (n = 10) and expanded disability status scale (EDSS) scores (n = 6). In acute ON, thinning of the GCL is measurable prior to RNFL thinning, and GCL thickness after 1-2 months may predict visual function after 6 months. Furthermore, GCL thinning occurs in MS both with and without prior ON, and may be associated with visual function and EDSS score. This suggests that the GCL is a promising biomarker, which may be used to examine in vivo neurodegeneration in ON and MS.

Hypoxic mechanisms in primary headaches.

Background Hypoxia causes secondary headaches such as high-altitude headache (HAH) and headache due to acute mountain sickness. These secondary headaches mimic primary headaches such as migraine, which suggests a common link. We review and discuss the possible role of hypoxia in migraine and cluster headache. Methods This narrative review investigates the current level of knowledge on the relation of hypoxia in migraine and cluster headache based on epidemiological and experimental studies. Findings Epidemiological studies suggest that living in high-altitude areas increases the risk of migraine and especially migraine with aura. Human provocation models show that hypoxia provokes migraine with and without aura, whereas cluster headache has not been reliably induced by hypoxia. Possible pathophysiological mechanisms include hypoxia-induced release of nitric oxide and calcitonin gene-related peptide, cortical spreading depression and leakage of the blood-brain barrier. Conclusion There is a possible link between hypoxia and migraine and maybe cluster headache, but the exact mechanism is currently unknown. Provocation models of hypoxia have yielded interesting results suggesting a novel approach to study in depth the mechanism underlying hypoxia and primary headaches.

Migraine induced by hypoxia: an MRI spectroscopy and angiography study.

Migraine with aura is prevalent in high-altitude populations suggesting an association between migraine aura and hypoxia. We investigated whether experimental hypoxia triggers migraine and aura attacks in patients suffering from migraine with aura. We also investigated the metabolic and vascular response to hypoxia. In a randomized double-blind crossover study design, 15 migraine with aura patients were exposed to 180 min of normobaric hypoxia (capillary oxygen saturation 70-75%) or sham on two separate days and 14 healthy controls were exposed to hypoxia. Glutamate and lactate concentrations in the visual cortex were measured by proton magnetic resonance spectroscopy. The circumference of cranial arteries was measured by 3 T high-resolution magnetic resonance angiography. Hypoxia induced migraine-like attacks in eight patients compared to one patient after sham (P = 0.039), aura in three and possible aura in 4 of 15 patients. Hypoxia did not change glutamate concentration in the visual cortex compared to sham, but increased lactate concentration (P = 0.028) and circumference of the cranial arteries (P < 0.05). We found no difference in the metabolic or vascular responses to hypoxia between migraine patients and controls. In conclusion, hypoxia induced migraine-like attacks with and without aura and dilated the cranial arteries in patients with migraine with aura. Hypoxia-induced attacks were not associated with altered concentration of glutamate or other metabolites. The present study suggests that hypoxia may provoke migraine headache and aura symptoms in some patients. The mechanisms behind the migraine-inducing effect of hypoxia should be further investigated.