Silvia Boschi

Genetic variants in the NOTCH4 gene influence the clinical features of migraine

BackgroundRecent studies suggested an important role for vascular factors in migraine etiopathogenesis. Notch4 belongs to a family of transmembrane receptors that play an important role in vascular development and maintenance. The aim of this study was to test the hypothesis that polymorphisms of the NOTCH4 gene would modify the occurrence and the clinical features of migraine.FindingsUsing a case–control strategy, we genotyped 239 migraine patients and 264 controls for three different non-synonymous polymorphisms (T320A, G835V, R1346P) of the NOTCH4 gene and for the (CTG) n-encoding polyleucine polymorphism in exon 1. Although the analyzed polymorphisms resulted not associated with migraine, the clinical characteristics of our patients were significantly influenced by the different NOTCH4 genotypes. Longer duration of disease and severity of neurovegetative symptoms during headache attacks were associated with the R1346P and G835V polymorphisms, respectively. In female patients, worsening of migraine symptoms at menarche was significantly correlated with T320A polymorphism.ConclusionsOur study shows that genetic variations within the NOTCH4 gene significantly modify the clinical characteristics of migraine and may have a role in disease pathogenesis.

Is HCRTR2 a Genetic Risk Factor for Alzheimer's Disease?

Backgrounds/Aims: Alzheimers disease (AD) is one of the main types of dementia affecting about 50-55% of all demented patients. Sleep disturbances in AD patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble the core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. The aim of our study was to investigate whether genetic variants in the hypocretin (HCRT) and in the hypocretin receptors 1 and 2 (HCRTR1, HCRTR2) genes could modify the occurrence and the clinical features of AD and to examine if these possible variants influence the role of the protein in sleep regulation. Methods: Using a case-control strategy, we genotyped 388 AD patients and 272 controls for 10 SNPs in the HCRT, HCRTR1 and HCRTR2 genes. In order to evaluate which residues belong to the HCRTR2 binding site, we built a molecular model. Results: The genotypic and allelic frequencies of the rs2653349 polymorphism were different (χ2 = 5.77, p = 0.016; χ2 = 6.728, p = 0.035) between AD patients and controls. The carriage of the G allele was associated with an increased AD risk (OR 2.53; 95% CI 1.10-5.80). No significant differences were found in the distribution of either genotypic or allelic frequencies between cases and controls in the HCRTR1 polymorphisms rs2271933, rs10914456 and rs4949449 and in the HCRTR2 polymorphism rs3122156. Conclusion: Our data support the hypothesis that the HCRTR2 gene is likely to be a risk factor for AD. The increased risk inferred is quite small, but in the context of a multi-factorial disease, the presence of this polymorphism may significantly contribute to influencing the susceptibility for AD by interacting with other unknown genetic or environmental factors in sleep regulation.

Lack of association between APOE gene polymorphisms and amyotrophic lateral sclerosis: a comprehensive meta-analysis.

Abstract Several studies have evaluated the association between APOE gene polymorphisms and the risk for amyotrophic lateral sclerosis (ALS), with inconclusive results. The aim of our study was to further define the risk associated with carriage of the APOE alleles and development and clinical characteristics of ALS. We performed a comprehensive meta-analysis of all existing studies investigating the association between the APOE gene and ALS published up to September 2013, comprising a total of 4249 ALS patients and 10,397 controls. Pooled odds ratios (OR) were estimated using the random effect (RE) model. Results showed that the carriage of different APOE alleles had no effect on disease risk. In particular, the ϵ4 allele was not associated with a significantly increased disease risk (ϵ4 carriers vs. non-ϵ4 carriers: RE OR 1.18; 95% CI 0.91–1.53). In conclusion, our study suggests that the APOE gene does not have a significant effect in ALS aetiopathogenesis.

Genetic analysis of CHCHD2 and CHCHD10 in Italian patients with Parkinson's disease

In recent years, CHCHD2 and CHCHD10 mutations were reported to be associated with a broad spectrum of neurodegenerative diseases, including Parkinsons disease (PD), although with conflicting results in different populations. The present study aimed to evaluate CHCHD2 and CHCHD10 coding variants in Italian patients with PD. All the coding regions and flanking intronic splice sites of CHCHD2 and CHCHD10 were sequenced. None of our 119 PD cases carried CHCHD2 mutations, whereas 1 sporadic PD patient showed the Pro34Ser substitution in CHCHD10. Our data suggest that CHCHD2 and CHCDH10 mutations are not a relevant cause of PD in Italian population.

Investigating the role of adipokines in chronic migraine.

Background and aims Adiponectin, leptin, and resistin are adipocyte-derived secretory factors involved in endothelial function, weight, inflammation, and insulin resistance. Recent studies suggested a role for adipokines in episodic migraine as mediators of inflammatory processes. The aim of this study was to investigate plasma concentrations of adiponectin, leptin, and resistin in patients with chronic migraine. Materials and methods Twenty-seven chronic migraineurs (20 females, 7 males; mean age 49.0 ± 9.0 yrs) and 37 healthy controls (23 females, 14 males; mean age 49.8 ± 15.0 yrs) were selected for the study. Fasting plasmatic levels of total adiponectin, leptin, and resistin were measured using ELISA kits during a pain-free period. Fasting glucose, insulin, total and HDL-cholesterol, triglycerides, and ESR were also determined. Results Serum levels of adiponectin and resistin were significantly increased in chronic migraineurs in comparison with controls (p = 0.001 and p = 0.032, respectively). After correction for BMI, sex and age, leptin levels were significantly increased in chronic migraineurs (p = 0.007). A positive correlation between leptin concentrations and both indices of insulin resistance and markers of inflammation was found. Discussion Our data suggest that adiponectin and resistin are altered in non-obese chronic migraineurs. Further studies are needed to elucidate the neurobiological mechanisms underlying adipokine dysfunction in migraine.

KCNK18 (TRESK) genetic variants in Italian patients with migraine.

To evaluate the prevalence of KCNK18 gene mutations in a dataset of Italian migraineurs, with and without aura, and in healthy controls, and to investigate in silico the functional effects of the mutations.

Magnetic Nanoparticles in the Central Nervous System: Targeting Principles, Applications and Safety Issues

One of the most challenging goals in pharmacological research is overcoming the Blood Brain Barrier (BBB) to deliver drugs to the Central Nervous System (CNS). The use of physical means, such as steady and alternating magnetic fields to drive nanocarriers with proper magnetic characteristics may prove to be a useful strategy. The present review aims at providing an up-to-date picture of the applications of magnetic-driven nanotheranostics agents to the CNS. Although well consolidated on physical ground, some of the techniques described herein are still under investigation on in vitro or in silico models, while others have already entered in—or are close to—clinical validation. The review provides a concise overview of the physical principles underlying the behavior of magnetic nanoparticles (MNPs) interacting with an external magnetic field. Thereafter we describe the physiological pathways by which a substance can reach the brain from the bloodstream and then we focus on those MNP applications that aim at a nondestructive crossing of the BBB such as static magnetic fields to facilitate the passage of drugs and alternating magnetic fields to increment BBB permeability by magnetic heating. In conclusion, we briefly cite the most notable biomedical applications of MNPs and some relevant remarks about their safety and potential toxicity.

O057. Altered plasma adipokines concentrations in chronic migraine

Background Adiponectin, leptin, and resistin are adipocyte-derived secretory factors which have functions in immune response, inflammation, endothelial function, overweight, and insulin resistance. Recently, adipokines have been suggested to contribute as inflammatory mediators of migraine. Clinical studies reported increases of adiponectin levels in migraineurs. Migraine pain severity and response to treatment in episodic migraine are associated with changes in both adiponectin and leptin concentrations. In addition, receptors for these adipokines are expressed in key structures implicated in migraine, including the hypothalamus and the cerebral microvasculature. The aim of this study was to investigate plasma concentrations of adiponectin, leptin, and resistin in patients with chronic migraine.