Stefano Zanigni

Family History for Chronic Headache and Drug Overuse as a Risk Factor for Headache Chronification

Objectives.— To assess whether family history for chronic headache (CH) and drug overuse could represent a risk factor for headache chronification.

Increased Prevalence of Sleep Disorders in Chronic Headache: A Case–Control Study

Objectives.— The aim of our study was to investigate the prevalence of sleep disorders in chronic headache patients and to evaluate the role of psychiatric comorbidity in the association between chronic headache and sleep complaints.

Overexpression of blood microRNAs 103a, 30b, and 29a in l-dopa–treated patients with PD

Objective: The aims of the present study were to profile the expression of several candidate microRNAs (miRNAs) in blood from l-dopa-treated and drug-naive patients with Parkinson disease (PD) vs unaffected controls and to interpret the miRNA expression data in a biological context. Methods: We analyzed RNAs from peripheral blood of 36 l-dopa–treated, 10 drug-naive patients with PD and unaffected controls matched 1:1 by sex and age. We evaluated expression by reverse transcription–quantitative real-time PCR, and we analyzed data using a 2-tailed paired t test. To detect miRNA targets, several miRNA resources were combined to generate an overall score for each candidate gene using weighted rank aggregation. Results: Significant overexpression of miR-103a-3p (p < 0.0001), miR-30b-5p (p = 0.002), and miR-29a-3p (p = 0.005) in treated patients with PD was observed, and promising candidate target genes for these were revealed by an integrated in silico analysis. Conclusions: We revealed 3 candidate biomarkers for PD. miRNAs 30b-5p and 29a-3p replicated a documented deregulation in PD albeit opposite to published data, while for miR-103a-3p, we demonstrated for the first time an overexpression in treated patients with PD. Expression studies in patients and/or in isolated peripheral blood mononuclear cells before and after l-dopa administration are necessary to define the involvement of l-dopa treatment in the observed overexpression. Our in silico analysis to prioritize targets of deregulated miRNAs identified candidate target genes, including genes related to neurodegeneration and PD. Despite the preliminary character of our study, the results provide a rationale for further clarifying the role of the identified miRNAs in the pathogenesis of PD and for validating their diagnostic potential.

Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

REM behaviour disorder and neurodegenerative diseases

Rapid-eye movement (REM) sleep behaviour disorder (RBD) is an REM sleep parasomnia characterized by enactment of dream content during REM sleep associated with loss of muscle atonia. RBD can be either idiopathic or secondary to drugs or other diseases. The best recognized association is with neurodegenerative diseases, namely alpha-synucleinopathies. RBD may represent the first feature of neurodegeneration and can be considered an early marker of these disorders. This review describes the main clinical, pathogenetic, and therapeutic features of RBD, pointing to its association with neurodegenerative diseases and emphasizing the clinical and prognostic implications.

Association between restless legs syndrome and migraine: A population-based study

A higher prevalence of restless legs syndrome (RLS) in migraineurs has been reported in clinical samples and in two large‐scale clinical trials performed on healthcare workers but general population‐based studies on this topic are lacking. The aim of this study was to assess the association between migraine and RLS in an Italian rural adult population‐based setting.

Association between restless legs syndrome and hypertension: A preliminary population-based study in South Tyrol, Italy

Restless legs syndrome (RLS) is a sleep‐related movement disorder characterized by an irresistible urge to move the legs accompanied by paresthesia and/or dysesthesia that begins or worsens in the evening and night and that is partially or totally relieved by movement. Many studies have investigated the association between RLS and cardiovascular risk factors, particularly hypertension, leading to conflicting results. The aim of this study was to assess the association between RLS and hypertension considering also other cardiovascular risk factors that could act as confounders.

The role of cardiac diseases in the comorbidity between migraine and stroke

Abstract.Several case-control and cohort studies have suggested an association between migraine and stroke. A significantly higher risk for stroke was found in women under the age of 45 years and for the subgroup with migraine with aura, the posterior circulation being significantly more frequently involved. The link between cardiac diseases and the comorbidity migraine–stroke has been evaluated considering both possible relationships: a higher prevalence of a vascular disease involving both heart and brain in migraineurs, or a cardiac disorder, more prevalent in migraineurs, with a possible aetiological role in migraine attacks.

Investigation of the T3111C CLOCK gene polymorphism in cluster headache.

Sirs: Cluster headache (CH) is a primary headache characterized by severe unilateral pain, ipsilateral autonomic symptoms and, in many cases, restlessness. The etiology of CH is still unclear, although clinical, endocrine and neuroimaging studies implicate the hypothalamus. Hypothalamic involvement is also supported by the efficacy of stereotactic deep brain stimulation of the posterior hypothalamic area in chronic drug resistant CH [1]. The increased familial risk of CH suggests a genetic liability with inheritance likely to be autosomal dominant with low penetrance, although autosomal recessive or multifactorial inheritance have also been suggested in some families [2]. A polymorphism of the hypocretin receptor 2 gene has recently been associated with CH [3], a remarkable association since hypocretin-containing cells are located exclusively in the posterolateral hypothalamus. A striking feature of CH is its diurnal and seasonal periodicity, suggesting that circadian and infradian rhythms regulate CH attacks. Polymorphisms in the CLOCK gene, a highly conserved circadian gene, influence the circadian phase in humans [4] and circadian mood fluctuations in bipolar patients [5]. We performed a genetic association study to evaluate whether the T3111C CLOCK polymorphism (also known as T3092C) might be related to CH susceptibility under the assumption of autosomal dominant inheritance. A total of 101 consecutive, unrelated Italian patients (79 men and 22 women) with CH (85 episodic and 16 chronic CH) gave informed consent to the study. All patients were diagnosed after direct interview by a neurologist expert in headache disorders and according to ICHD-II criteria [6]. Of the 101 patients, 87 described a clear circadian rhythmicity of the attacks. 100 healthy individuals, in whom CH and migraine were excluded by direct interview, served as controls. The control sample came from the same geographical region as the CH patients. We analyzed a single nucleotide polymorphism, T3111C, in the 3’ flanking region of the CLOCK gene [4]. DNA was extracted from whole blood by standard methods [7]. PCR primers and methods were those reported by Katzenberg et al. [4]. The T3111C polymorphism was detected by enzymatic digestion with Sdu I (Fermentas) and electrophoresed on MetaPhor agarose 2 % gel. The allelic and genotypic frequencies were compared by means of the Fisher’s exact test. The Hardy-Weinberg equilibrium was verified for all tested populations, and alleles were in Hardy-Weinberg equilibrium in both controls and patients. We found no significant difference in allelic and genotypic frequencies between the total CH patient group and the control subjects (χ2 = 1.261, p = 0.261; χ2 = 5.791, p = 0.055) (Table 1). Nor was a significant difference found when considering the 87 CH patients with circadian rhythmicity of the attacks alone. Our study does not support the hypothesis that the T3111C CLOCK polymorphism is associated with CH. It therefore strengthens the similar negative results reported previously by Rianero et al. [8]. Our analysis moreover resulted in nonsignificant differences when the 87 CH patients reporting a clear periodicity of the attacks were considered separately. It thus appears that CLOCK gene T3111C polymorphism does not influence CH, but our result of course cannot exclude that polymorphic variations at other biological rhythm genes LETTER TO THE EDITORS

Application of ICHD-II and revised diagnostic criteria to patients with chronic daily headache

The objective of this study was to evaluate how the criteria of the second edition of the International Classification of Headache Disorders (ICHD-II) and the revised criteria fit a sample of patients with chronic daily headache (CDH). One hundred and five patients with CDH in a tertiary headache centre were included. Headache was assessed using a semi-structured interview. Patients were classified according to the ICHD-II and to the new appendix criteria of the ICHD. Using the ICHDII, 91% of patients received a combination of diagnoses and 76% received only a probable diagnosis: 47% had probable chronic migraine (CM) with probable medication overuse headache (MOH), 28% had probable chronic tension-type headache (CTTH) with probable MOH, 20% had CTTH and 3.8% had CM. Using the new appendix criteria, 88.5% of patients required one diagnosis. Seventy-six percent of patients were classified as MOH, 17% had CTTH and 6.7% had CM. The classification of CDH remains controversial. Alternative criteria for CM with and without medication overuse are discussed.