The Management of High-Frequency Episodic and Chronic Migraines with Calcitonin Gene-Related Peptide Monoclonal Antibody

Introduction. High prevalence of migraine and its impact on quality of life requires the development of original agents. In 2020, fremanezumab, a new calcitonin gene-related peptide monoclonal antibody was authorized in Russia. Objective: to evaluate safety and effectiveness of fremanezumab in patients with high-frequency episodic migraine (HF EM) and chronic migraine (CM). Materials and methods. We assessed 60 patients at the age of 35.5 8.96 years (85%, females) with HFEM and CM with and without aura who were either receiving preventive treatment or not. Fremanezumab was administered subcutaneously at a single dose of 675 mg. The study participants were followed-up for efficacy in 3 months. The investigators assessed change in the number of days with headache per month as well as headache intensity, its impact on the daily activities, anxiety, and depression. Results. By the end of month 3 post dosing, the number of days with headache decreased by 50% in 76.7% of participants where 77.8% of individuals suffered from HF EM and 72.7% of individuals had CM while headache intensity decreased in all the patients equally. No response (decrease in the number of days with headache by 30%) was reported in 15% of participants including 14.8% of individuals with HF EM and 15.2% of individuals with CM. By the end of study month 3, 81% of participants demonstrated no anxiety symptoms and 79% of participants showed no depression with significant MIDAS and HIT-6 score decline in both groups. Only 3 (5%) patients noted adverse events (redness, itching at the administration site). Conclusion. We documented higher fremanezumab safety and effectiveness in patients with EM and CM in real-world practice as compared to fremanezumab safety and efficacy in randomized clinical trials. A single dose of fremanezumab (675 mg) resulted in effective migraine prevention, decline in comorbid anxiety and depression, and improved quality of life during 3-month follow-up

Vitamin D binding protein polymorphysm in patients with acute coronary syndrome in kaliningrad region

BACKGROUND: Vitamin D binding protein is a main vitamin D carrier in serum. It also has an impact on macrophagial function. Role of vitamin D and macrophages in the pathogenesis of atherosclerosis is scientifically proven but there is lack of data on vitamin D binding protein in this regard. AIMS: To evaluate the vitamin D binding protein polymorphism in patients with acute coronary syndrome without diabetes mellitus, autoimmune diseases and malignant tumors. Determine correlation, if there is, between vitamin D binding protein allele and features of acute coronary syndrome among this patient group. MATERIALS AND METHODS: It is a cross-sectional observational study. Study subjects are patients with acute coronary syndrome. Exclusion criteria are the presence of diabetes mellitus, autoimmune diseases and malignant tumors. In all participants were evaluated: predisposing factors for heart diseases, CBC, biochemical blood test, troponin, coronarography, echocardiography. The study lasted for 5 months from November 2017 until March 2018. Primary end point – assessment of vitamin D binding protein polymorphysm in this group of patients with acute coronary syndrome by means of vitamin D binding protein gene sequencing. 50 patients were enrolled into this study who were urgently admitted to hospital and diagnosed with acute coronary syndrome. Among them – 36 males and 14 females. Mean age was 60 (55;66) years. All participants were sequenced for single nucleotide polymorphysm in VDBP p.T436K (rs4588) and P.432E (rs7041). RESULTS: Gene polymorphysms of interest were found in 43 patients among 50 enrolled. Haplotype Gc1s/2 (rs7041G-rs4588A) was found in 7 (14%) patients, Gc2 (rs7041T-rs4588A) — in 9 (18%) patients, Gc1s (rs7041G-rs4588C) – in 20 (40%) patients, Gc1f (rs7041T-rs4588C) in 14 (28%). Coronarography showed that coronary artery occlusions obstructing more than 50% of vessel lumen was found in 16 patients; obstruction greater than 90% was seen in 8 patients; total occlusion – in 4 patients. CONCLUSIONS: In patient group with acute coronary syndrome prevalence of vitamin D binding protein gene polymorphysm was high – in 86% of participants. The features of Gc2 haplotype were higher frequency of recurrent myocardial infarction and total coronary artery occlusion, as well as tendency to decreased serum vitamin D3 (25(OH)D) levels

Biochemical markers of neurodegeneration in patients with cerebral small vessel disease and Alzheimer's disease

Introduction. Cerebral small vessel disease (CSVD) as well as the Alzheimer's disease (AD) and their comorbidities are the most common causes of cognitive impairments (CIs). Objective: to evaluate the predictive power of the biochemical neurodegeneration markers in patients with CSVD and AD. Materials and methods. We assessed the following neurodegeneration markers in 68 patients with CSVD (61.0 8.6 years; 60.3% males), 17 patients with AD (65.2 8.3 years; 35.3% males), and 26 healthy volunteers (59.9 6.7 years; 38.5% males): neuron-specific enolase (NSE), glial fibrillary acid protein (GFAP), neurofilament light polypeptide (NEFL) in blood (for all patients) and in cerebrospinal fluid (CSF; in patients with CSVD and AD). We assessed the predictive power of those markers with ROC analysis. Results. As compared to the control group, serum GFAP in patients with CSVD showed its predictive power at 0.155 ng/ml (sensitivity 74%; specificity 70%). Serum NEFL 0.0185 ng/ml (sensitivity 82%; specificity 96%) and NSE 4.95 g/ml (sensitivity 77%; specificity 71%) showed their predictive power in patients with AD. CSF GFAP 1.03 ng/ml (sensitivity 84%; specificity 88%), CSF NSE 19.10 g/ml (sensitivity 88%; specificity 91%), serum NEFL 0.021 ng/ml (sensitivity 71%; specificity 76%), serum NSE /CSF NSE ratio 0.273 ng/ml (sensitivity 87%; specificity 88%) help differentiate CSVD from AD. Conclusions. We found that serum GFAP can be a useful diagnostic marker in patients with CSVD, while serum NEFL and serum NSE can help identify the AD. In addition, CSF GFAP and CSF NSE as well as serum NEFL and serum NSE/CSF NSE can help differentiate CSVD from AD. We can use those markers in clinical and research practice to identify the vascular and neurodegenerative causes of CIs and their comorbidities, which is of a great importance in developing specific treatment and predicting the course of the disease

Survival, cognitive functions, and brain MRI in patients with cSVD: 5-year observation

Introduction. Contributing to high disability and mortality, cerebral small vessel disease (cSVD) is a common condition in senior and elderly individuals. Objective: to assess the 5-year survival as well as cognitive and MRI changes in patients with cSVD and cognitive impairment (CI). Materials and methods. A prospective 5-year study included 54 patients (of them 37 women; mean age: 60.51 6.76 years) with cSVD, CIs, and white matter hyperintensities (WMHs; Fazekas 23). Twenty-two subjects were followed up to assess cognitive functions and a type of CI, cSVD MRI features, WMH, white and grey matter, and cerebrospinal fluid (CSF) volume as well as microstructural brain changes and correlate cognitive and MRI parameters at 5 years timepoint after the baseline. Results. Dementia developed in 14% of the subjects and 14% of the subjects died over a 5-year period. The subjects assessed twice had controlled hypertension (HTN). CIs worsened in the domain of executive functions and memory with mixed-type CI worsening. The follow-up showed that the WMH and CSF volume increased while the white matter volume decreased and axial diffusivity increased in the corpus callosum. The CSF volume correlated with the Stroop Test results and delayed memory (r = 0.803 and r = 0.701, respectively) and with white matter atrophy (r = 0.256) while the latter correlated with the axial diffusivity increased in the corpus callosum (r = 0.560). Conclusion. cSVD with advanced WMHs is associated with high mortality and dementia progression. General cognition assessment and MRI scan are not enough sensitive to assess disorder progression over a 5-year period. Stroop Test and Delayed 10-Word Recall Test results and transition to mixed-type CI indicate CI worsening and, therefore, can be used for the follow-up assessment. Cognitive decline in extensive cSVD is mediated by the brain matter atrophy and altered CSF circulation

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions

The Predictive Value of Salt Sensitivity and Osmotic Fragility in the Development of Cerebral Small Vessel Disease

Increased salt intake in food probably affects the progression of cerebral small vessel disease (CSVD), which justifies the study of disturbances in sodium homeostasis associated with the development of CSVD. We aimed to clarify the role of salt sensitivity and osmotic fragility in the development of CSVD. Erythrocyte salt sensitivity was measured using the modified salt blood test, and osmotic fragility was measured using the classic osmotic fragility test in 73 patients with CSVD (48 women; 60.1 ± 6.5 years) and 19 healthy volunteers (14 women; 56.9 ± 6.4 years). Salt sensitivity and osmotic fragility exhibited a predictive value in relation to CSVD. These parameters were associated with an increase in white matter hyperintensities (p = 0.019 and 0.004, respectively). Their simultaneous use increased their predictive ability for CSVD (p < 0.000001; AUC (95% CI), 0.824 (0.724–0.923)). The possibility of predicting CSVD using erythrocyte salt sensitivity and osmotic fragility indicates the value of the individual glycocalyx buffer capacity in relation to sodium and the activity of sodium channels in the development of CSVD. Increased salt sensitivity and osmotic fragility seem to be risk factors for CSVD

Tissue Plasminogen Activator and MRI Signs of Cerebral Small Vessel Disease

Cerebral small vessel disease (SVD) is one of the leading causes of cognitive impairment and stroke. The importance of endothelial dysfunction and high blood–brain barrier (BBB) permeability in pathogenesis, together with ischemia, is under discussion. The aim of this study was to clarify the relationship between tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), and magnetic resonance imaging (MRI) signs of SVD. We examined 71 patients (23 men and 48 women; mean age: 60.5 ± 6.9 years) with clinical and MRI signs of SVD, and 21 healthy volunteers with normal MRIs. All subjects underwent 3T MRI and measurements of t-PA and PAI-1 levels. An increase in t-PA level is correlated with the volume of white matter hyperintensities (WMH) (R = 0.289, p = 0.034), severity on the Fazekas scale (p = 0.000), and with the size of subcortical (p = 0.002) and semiovale (p = 0.008) perivascular spaces. The PAI-1 level is not correlated with the t-PA level or MRI signs of SVD. The correlation between t-PA and the degree of WMH and perivascular spaces’ enlargement, without a correlation with PAI-1 and lacunes, is consistent with the importance of t-PA in BBB disruption and its role in causing brain damage in SVD

MRI Types of Cerebral Small Vessel Disease and Circulating Markers of Vascular Wall Damage

The evaluation of the clustering of magnetic resonance imaging (MRI) signs into MRI types and their relationship with circulating markers of vascular wall damage were performed in 96 patients with cerebral small vessel disease (cSVD) (31 men and 65 women; mean age, 60.91 ± 6.57 years). The serum concentrations of the tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor-A (VEGF-A), and hypoxia-inducible factor 1-α (HIF-1α) were investigated in 70 patients with Fazekas stages 2 and 3 of white matter hyperintensities (WMH) and 21 age- and sex-matched volunteers with normal brain MRI using ELISA. The cluster analysis excluded two patients from the further analysis due to restrictions in their scanning protocol. MRI signs of 94 patients were distributed into two clusters. In the first group there were 18 patients with Fazekas 3 stage WMH. The second group consisted of 76 patients with WMH of different stages. The uneven distribution of patients between clusters limited the subsequent steps of statistical analysis; therefore, a cluster comparison was performed in patients with Fazekas stage 3 WMH, designated as MRI type 1 and type 2 of Fazekas 3 stage. There were no differences in age, sex, degree of hypertension, or other risk factors. MRI type 1 had significantly more widespread WMH, lacunes in many areas, microbleeds, atrophy, severe cognitive and gait impairments, and was associated with downregulation of VEGF-A compared with MRI type 2. MRI type 2 had more severe deep WMH, lacunes in the white matter, no microbleeds or atrophy, and less severe clinical manifestations and was associated with upregulation of TNF-α compared with MRI type 1. The established differences reflect the pathogenetic heterogeneity of cSVD and explain the variations in the clinical manifestations observed in Fazekas stage 3 of this disease