Alessandra Frustaci

Meta-Analysis of the Brain-Derived Neurotrophic Factor Gene (BDNF) Val66Met Polymorphism in Anxiety Disorders and Anxiety-Related Personality Traits

Objective: Brain-derived neurotrophic factor (BDNF) is potentially involved in the pathogenesis of anxiety. We carried out meta-analyses to evaluate the relationship between the BDNF Val66Met (valine, methionine) polymorphism and anxiety disorders (AD) or anxiety-related personality traits (ARPT). Methods: Medline, Embase and PsycINFO were searched up to December 2007. We investigated 3 outcomes related to BDNF Val66Met polymorphisms: (1) clinically diagnosed cases of AD; (2) ARPT in subjects without psychiatric diagnoses, assessed either by the Neuroticism scale of NEO-Personality Inventory forms (NEO-PI, NEO-PI-R, NEO-FFI), or by (3) the Harm Avoidance (HA) scale of Tridimensional Personality Questionnaire (TPQ) or its extended version Temperament and Character Inventory (TCI). Results: Seven case-control studies were selected for AD, including 1,092 cases and 8,394 controls, while 5 cross-sectional studies for Neuroticism (n = 1,633) and 4 for HA (n = 607). Both Met/Met and Val/Met individuals, as compared to Val/Val, showed a statistically significant lower Neuroticism score [SMD = –0.24 (95% CI: –0.44, –0.04), and –0.11 (95% CI: –0.22, –0.01), respectively]. No significant association was found between BDNF Val66Met polymorphism and AD [OR = 1.13 (95% CI: 0.85–1.52) for Met/Met versus Val/Val] or HA [SMD = 0.11 (95% CI: –0.19, 0.42) for Met/Met vs. Val/Val]. Conclusions: The low number of studies on this topic and their limited sample size, along with the inner limits in the definition of anxiety phenotypes, suggest caution in the interpretation of these results. Larger additional studies possibly investigating the interaction with other genes and environmental exposures are required to confirm these results.

Pregabalin in outpatient detoxification of subjects with mild-to-moderate alcohol withdrawal syndrome.

In this open, prospective study we aimed to investigate the efficacy, medical safety and practicability of pregabalin in outpatient detoxification of alcohol‐dependent patients with mild‐to‐moderate alcohol withdrawal syndrome (AWS). Craving reduction, improvement of psychiatric symptoms and quality of life were the secondary endpoints.

A systems medicine clinical platform for understanding and managing non- communicable diseases

Non-Communicable Diseases (NCDs) are among the most pressing global health problems of the twenty-first century. Their rising incidence and prevalence is linked to severe morbidity and mortality, and they are putting economic and managerial pressure on healthcare systems around the world. Moreover, NCDs are impeding healthy aging by negatively affecting the quality of life of a growing number of the global population. NCDs result from the interaction of various genetic, environmental and habitual factors, and cluster in complex ways, making the complex identification of resulting phenotypes not only difficult, but also a top research priority. The degree of complexity required to interpret large patient datasets generated by advanced high-throughput functional genomics assays has now increased to the point that novel computational biology approaches are essential to extract information that is relevant to the clinical decision-making process. Consequently, system-level models that interpret the interactions between extensive tissues, cellular and molecular measurements and clinical features are also being created to identify new disease phenotypes, so that disease definition and treatment are optimized, and novel therapeutic targets discovered. Likewise, Systems Medicine (SM) platforms applied to extensively-characterized patients provide a basis for more targeted clinical trials, and represent a promising tool to achieve better prevention and patient care, thereby promoting healthy aging globally. The present paper: (1) reviews the novel systems approaches to NCDs; (2) discusses how to move efficiently from Systems Biology to Systems Medicine; and (3) presents the scientific and clinical background of the San Raffaele Systems Medicine Platform.

Factors associated with a negative outcome of medication-overuse headache: A 3-year follow-up (the ‘CARE’ protocol)

Aim To evaluate factors associated with a negative outcome in a 3-year follow-up of subjects diagnosed with medication-overuse headache (MOH) (revised-ICHD-II criteria). Methods All consecutive patients entering the center’s inpatient detoxification program were analyzed in a prospective, non-randomized fashion. All participants were assessed by a neurologist using an ad hoc patient record form. Personality was assessed using the Minnesota Multiphasic Personality Inventory (MMPI)-2, Chi-square test, one-way analysis of variance (ANOVA), and odds ratios (OR) were calculated as appropriate. Results One-hundred and fifty patients completed the follow-up (79.3% females, age 46.40 ± 11.31 years): 13 never stopped their drug overuse (A), 38 stopped their overuse, but relapsed at least once (B), and 99 stopped and never relapsed (C). The Group A patients differed from those in B + C as they were more frequently single (OR 0.134; p = 0.007) and unemployed (OR 3.273; p = 0.04), took a higher number of drug doses (p < 0.001), and less frequently drank coffee (OR 3.273; p = 0.044). Personality profile: subjects in A scored higher than those in C on the following scales: Hypochondriasis (p = 0.007), Depression (p = 0.003), Paranoia (p = 0.025), Fears (p = 0.003), Obsessiveness (p = 0.026), Bizarre Mentation (p = 0.046), Social Discomfort (p = 0.004), Negative Treatment Indicators (p = 0.040), Repression (p = 0.007), Overcontrolled Hostility (p = 0.040), Addiction Admission (p = 0.021), Social Responsibility (p = 0.039), and Marital Distress (p = 0.028). Conclusion Disease outcome in MOH patients is influenced negatively by overuse severity and by specific psychological and socio-economic variables. Other possible modifier factors were voluptuary habits.

DNA damage in non-communicable diseases: A clinical and epidemiological perspective

Non-communicable diseases (NCDs) are a leading cause of death and disability, representing 63% of the total death number worldwide. A characteristic phenotype of these diseases is the accelerated aging, which is the result of phenomena such as accumulated DNA damage, telomere capping loss and subcellular irreversible/nonrepaired oxidative damage. DNA damage, mostly oxidative, plays a key role in the development of most common NCDs. The present review will gather some of the most relevant knowledge concerning the presence of DNA damage in NCDs focusing on cardiovascular diseases, diabetes, chronic obstructive pulmonary disease, and neurodegenerative disorders, and discussing a selection of papers from the most informative literature. The challenge of comorbidity and the potential offered by new systems approaches for introducing these biomarkers into the clinical decision process will be discussed. Systems Medicine platforms represent the most suitable approach to personalized medicine, enabling to identify new patterns in the pathogenesis, diagnosis and prognosis of chronic diseases.

Beyond Acetylcholinesterase Inhibitors for Treating Alzheimer's Disease: α7-nAChR Agonists in Human Clinical Trials

The neuronal nicotinic alpha7-acetylcholine receptor (α7-nAChR) is a promising and attractive drug target for improving cognitive deficits in neuropsychiatric and neurological disorders such as Alzheimers disease (AD). α7-nAChR belongs to the family of ligand gated ion channels. α7-nAChR is expressed in key brain regions (e.g. pre- and frontal cortex, hippocampus). It is involved in essential cognitive functions such as memory, thinking, comprehension, learning capacity, calculation, orientation, language, and judgment. α7-nAChR binds to amyloid peptide (Aβ) inducing either receptor activation or inhibition in an Aβ concentration-dependent mode. Aβ oligomers induce τ phosphorylation via α7-nAChR activation. α7-nAChR agonists and/or α7-nAChR positive allosteric modulators may be useful in AD therapy. The current review enlightens: (i) α7-nAChR neurobiology, (ii) α7-nAChR role in cognition and (iii) in AD, and (iv) the clinical status of the most promising molecules for the treatment of cognitive dysfunction in AD.

Differences in the personality profile of medication-overuse headache sufferers and drug addict patients: a comparative study using MMPI-2.

(Headache 2011;51:1212‐1227)

The assessment of post-detoxification anhedonia: influence of clinical and psychosocial variables

Anhedonia, or the inability to experience pleasure, may be regarded either as a temperamental trait or as a state symptom of negative schizophrenia or melancholic depression. In substance use disorders, anhedonia was linked to hypoactivity of the dopaminergic mesolimbic system during protracted withdrawal. The authors investigated the influence of recent clinical and social-environmental factors on the hedonic capability and related psychopathology in a sample of 70 patients manifesting substance dependence (alcohol, opiates, multiple drugs) without severe comorbidity. Three symptom scales covering anhedonia (Snaith-Hamilton Pleasure Scale, SHAPS; Scale for the Assessment of Negative Symptoms, SANS; Bech-Rafaelsen Melancholia Scale, BRMES) were administered together with the European adaptation of the Addiction Severity Index (EuropASI). The composite scores from the seven areas of the EuropASI were introduced as independent factors in a stepwise regression analysis having symptom scores of anhedonia as dependent variables. Overall, the EuropASI composites do not explain the variability of the scores of anhedonia. Only in few cases, the regression models show a weak predictive capacity for medical status, alcohol use, and drug use composite scores, with R-square values ranging from 10 to 22%. Even if the studys limitations are noted, anhedonia appears as a psychopathological entity independent from other clinical and psychosocial features of treated addicts.

A meta-analysis of biomarkers related to oxidative stress and nitric oxide pathway in migraine

Background Oxidative and nitrosative stress are considered key events in the still unclear pathophysiology of migraine. Methods Studies comparing the level of biomarkers related to nitric oxide (NO) pathway/oxidative stress in the blood/urine of migraineurs vs. unaffected controls were extracted from the PubMed database. Summary estimates of mean ratios (MR) were carried out whenever a minimum of three papers were available. Nineteen studies were included in the meta-analyses, accounting for more than 1000 patients and controls, and compared with existing literature. Results Most studies measuring superoxide dismutase (SOD) showed lower activity in cases, although the meta-analysis in erythrocytes gave null results. On the contrary, plasma levels of thiobarbituric acid reactive substances (TBARS), an aspecific biomarker of oxidative damage, showed a meta-MR of 2.20 (95% CI: 1.65–2.93). As for NOs, no significant results were found in plasma, serum and urine. However, higher levels were shown during attacks, in patients with aura, and an effect of diet was found. The analysis of glutathione precursor homocysteine and asymmetric dimethylarginine (ADMA), an NO synthase inhibitor, gave inconclusive results. Conclusions The role of the oxidative pathway in migraine is still uncertain. Interesting evidence emerged for TBARS and SOD, and concerning the possible role of diet in the control of NOx levels.

From traditional European medicine to discovery of new drug candidates for the treatment of dementia and Alzheimer's disease: acetylcholinesterase inhibitors.

The leading Alzheimers disease (AD) therapeutics to date involves inhibitors of acetylcholinesterase (AChE), which should, in principle, elevate cholinergic signaling and limit inflammation. In spite of the effectiveness in 20%-30% of AD patients, more attention has been paid to find new anti-AChE agents from medicinal plants. Galanthamine, contained in the bulbs and flowers of Galanthus and related genera like Narcissus, represents a good example. The aim of this study is to review the role of possible AChE inhibitors (AChEI) present in plants traditionally used in European medicine for improving memory. Starting from Galanthamine, properties of Melissa species, Salvia officinalis, Arnica chamissonis and Ruta graveolens are discussed to point to the role of these plants as potential sources for the development of therapeutic agents for AD.