Role of Dopaminergic and Noradrenergic Systems as Potential Biomarkers in ADHD Diagnosis and Treatment

This chapter aims to identify, among the dopaminergic and noradrenergic molecules strongly associated to aetiopathogenesis of the disorder, potential genetic and biochemical markers linked to ADHD diagnosis and to assess whether treatments can change peripheral levels of a biomarker, to be then useful, if tested, as a response predictor

Neurodevelopmental disorders: Metallomics studies for the identification of potential biomarkers associated to diagnosis and treatment

Abstract Background Diagnosis and treatment of complex diseases such as Neurodevelopmental Disorders (NDDs) can be resolved through the identification of biomarkers. Metallomics (research on biometals) and metallomes (metalloproteins/metalloenzymes/chaperones) along with genomics, proteomics and metabolomics, can contribute to accelerate and improve this process. Aim This review focused on four NDDs pathologies (Schizophrenia, SZ; Attention Deficit Hyperactivity Disorder, ADHD; Autism, ADS; Epilepsy), and we reported, for the first time, different studies on the role played by the principal six essential trace elements (Cobalt, Co; Copper, Cu; Iron, Fe; Manganese, Mn; Selenium, Se; Zinc, Zn) that can influence diagnosis/treatment. Results in light of the literature presented, based on meta-analyses, we suggest that Zn (glutamatergic neurotransmission, inflammation, neurodegeneration, autoimmunity alterations), could be a potential diagnostic biomarker associated to SZ. Moreover, considering the single association studies going in the same direction, increased Cu (catecholamine alterations, glucose intolerance, altered lipid metabolism/oxidative stress) and lower Fe (dopaminergic dysfunctions) levels were associated with a specific negative symptomatology. Lower Mn (lipid metabolism/oxidative stress alterations), and lower Se (metabolic syndrome) were linked to SZ. From the meta-analyses in ADHD, it is evidenced that Fe (and ferritin in particular), Mn, and Zn (oxidative stress dysfunctions) could be potential diagnostic biomarkers, mainly associated to severe hyperactive or inattentive symptoms; as well as Cu, Fe, Zn in ADS and Zn in Epilepsy. Fe, Zn and Mn levels seem to be influenced by antipsychotics treatment in SZ; Mn and Zn by methylphenidate treatment in ADHD; Cu and Zn by antiepileptic drugs in Epilepsy. Conclusions Although there is controversy and further studies are needed, this work summarizes the state of art of the literature on this topic. We claim to avoid underreporting the impact of essential trace elements in paving the way for biomarkers research for NDDs

molecular mechanisms in cognitive frailty potential therapeutic targets for oxygen ozone treatment

Abstract In the last decade, cognitive frailty has gained great attention from the scientific community. It is characterized by high inflammation and oxidant state, endocrine and metabolic alterations, mitochondria dysfunctions and slowdown in regenerative processes and immune system, with a complex and multifactorial aetiology. Although several treatments are available, challenges regarding the efficacy and the costs persist. Here, we proposed an alternative non-pharmacological, non-side-effect, low cost therapy based on anti-inflammation, antioxidant, regenerative and anti-pathogens properties of ozone (O3), through the activation of several molecular mechanisms (Nrf2-ARE, NF-κB, NFAT, AP-1, HIFα). We highlighted how these specific processes could be implicated in cognitive frailty to identify putative therapeutic targets for its treatment. The O2-O3 therapy has never been tested for cognitive frailty. This work provides thus wide scientific background to build a consistent rationale for testing for the first time this therapy, that could modulate the immune, inflammatory, oxidant, metabolic, endocrine, microbiota and regenerative processes impaired in cognitive frailty. Although insights are needed, the O2-O3 therapy could represent a faster, easier, inexpensive monodomain intervention, working in absence of side effects, for cognitive frailty

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence

Cellular senescence is an irreversible state of cell cycle arrest occurring in response to stressful stimuli, such as telomere attrition, DNA damage, reactive oxygen species, and oncogenic proteins. Although beneficial and protective in several physiological processes, an excessive senescent cell burden has been involved in various pathological conditions including aging, tissue dysfunction and chronic diseases. Oxidative stress (OS) can drive senescence due to a loss of balance between pro-oxidant stimuli and antioxidant defences. Therefore, the identification and characterization of antioxidant compounds capable of preventing or counteracting the senescent phenotype is of major interest. However, despite the considerable number of studies, a comprehensive overview of the main antioxidant molecules capable of counteracting OS-induced senescence is still lacking. Here, besides a brief description of the molecular mechanisms implicated in OS-mediated aging, we review and discuss the role of enzymes, mitochondria-targeting compounds, vitamins, carotenoids, organosulfur compounds, nitrogen non-protein molecules, minerals, flavonoids, and non-flavonoids as antioxidant compounds with an anti-aging potential, therefore offering insights into innovative lifespan-extending approaches

The influence of psychiatric screening in healthy populations selection: a new study and meta-analysis of functional 5-HTTLPR and rs25531 polymorphisms and anxiety-related personality traits

<p>Abstract</p> <p>Background</p> <p>A genetic liability for anxiety-related personality traits in healthy subjects has been associated with the functional serotonin transporter promoter polymorphism (5-HTTLPR), although the data are somewhat conflicting. Moreover, only one study has investigated the functional significance of the 5-HTTLPR/rs25531 haplotypes in relation to anxiety traits in healthy subjects. We tested whether the 5-HTTLPR polymorphism and the 5-HTTLPR/rs25531 haplotypes are linked to Harm Avoidance (HA) using an association study (STUDY I) and a meta-analytic approach (STUDY II).</p> <p>Methods</p> <p>STUDY I: A total of 287 unrelated Italian volunteers were screened for DSM-IV Axis I disorders and genotyped for the 5-HTTLPR and rs25531 (A/G) polymorphisms. Different functional haplotype combinations were also analyzed. STUDY II: A total of 44 studies were chosen for a meta-analysis of the putative association between 5-HTTLPR and anxiety-related personality traits.</p> <p>Results</p> <p>STUDY I: In the whole sample of 287 volunteers, we found that the SS genotype and S'S' haplotypes were associated with higher scores on HA. However, because the screening assessed by Mini-International Neuropsychiatric Interview (M.I.N.I.) showed the presence of 55 volunteers affected by depression or anxiety disorders, we analyzed the two groups ("disordered" and "healthy") separately. The data obtained did indeed confirm that in the "healthy" group, the significant effects of the SS genotype and S'S' haplotypes were lost, but they remained in the "disordered" group. STUDY II: The results of the 5-HTTLPR meta-analysis with anxiety-related traits in the whole sample confirmed the association of the SS genotype with higher anxiety-related traits scores in Caucasoids; however, when we analyzed only those studies that used structured psychiatric screening, no association was found.</p> <p>Conclusions</p> <p>This study demonstrates the relevance to perform analyses on personality traits only in DSM-IV axis I disorder-free subjects. Furthermore, we did not find an association between functional serotonin transporter gene polymorphisms and anxiety traits in healthy subjects screened through a structured psychiatric interview.</p

Behavioral and Psychological Symptoms of Dementia (BPSD): Clinical Characterization and Genetic Correlates in an Italian Alzheimer’s Disease Cohort

Background: The occurrence of Behavioral and Psychological Symptoms of Dementia (BPSD) in Alzheimer&rsquo;s Disease (AD) patients hampers the clinical management and exacerbates the burden for caregivers. The definition of the clinical distribution of BPSD symptoms, and the extent to which symptoms are genetically determined, are still open to debate. Moreover, genetic factors that underline BPSD symptoms still need to be identified. Purpose. To characterize our Italian AD cohort according to specific BPSD symptoms as well as to endophenotypes. To evaluate the associations between the considered BPSD traits and COMT, MTHFR, and APOE genetic variants. Methods. AD patients (n = 362) underwent neuropsychological examination and genotyping. BPSD were assessed with the Neuropsychiatric Inventory scale. Results. APOE and MTHFR variants were significantly associated with specific single BPSD symptoms. Furthermore, &ldquo;Psychosis&rdquo; and &ldquo;Hyperactivity&rdquo; resulted in the most severe endophenotypes, with APOE and MTHFR implicated as both single risk factors and &ldquo;genexgene&rdquo; interactions. Conclusions. We strongly suggest the combined use of both BPSD single symptoms/endophenotypes and the &ldquo;genexgene&rdquo; interactions as valid strategies for expanding the knowledge about the BPSD aetiopathogenetic mechanisms

Common and specific genes and peripheral biomarkers in children and adults with attention-deficit/hyperactivity disorder

<p><b>Objectives:</b> Elucidating the biological mechanisms involved in attention-deficit/hyperactivity disorder (ADHD) has been challenging. Relatively unexplored is the fact that these mechanisms can differ with age.</p> <p><b>Methods:</b> We present an overview on the major differences between children and adults with ADHD, describing several studies from genomics to metabolomics performed in ADHD children and in adults (cADHD and aADHD, respectively). A systematic search (up until February 2016) was conducted.</p> <p><b>Results:</b> From a PRISMA flow-chart, a total of 350 and 91 genomics and metabolomics studies were found to be elligible for cADHD and aADHD, respectively. For children, associations were found for genes belonging to dopaminergic (SLC6A3, DRD4 and MAOA) and neurodevelopmental (LPHN3 and DIRAS2) systems and OPRM1 (Yates corrected <i>P</i> = 0.016; OR = 2.27 95%CI: 1.15–4.47). Studies of adults have implicated circadian rhythms genes, HTR2A, MAOB and a more generic neurodevelopmental/neurite outgrowth network (BCHE, SNAP25, BAIAP2, NOS1/NO, KCNIP4 and SPOCK3; Yates corrected <i>P</i> = 0.007; OR = 3.30 95%CI: 1.33–8.29). In common among cADHD and aADHD, the most significant findings are for oxidative stress proteins (MAD, SOD, PON1, ARES, TOS, TAS and OSI), and, in the second level, DISC1, DBH, DDC, microRNA and adiponectin.</p> <p><b>Conclusions:</b> Through a convergent functional genomics, this review contributes to clarification of which genetic/biological mechanisms differ with age. The effects of some genes do not change throughout the lifetime, whereas others are linked to age-specific stages. Additional research and further studies are needed to generate firmer conclusions that might someday be useful for predicting the remission and persistence of the disorder. Despite the limitations, some of these genes/proteins could be potential useful biomarkers to discriminate cADHD from aADHD.</p

Effects of intravenous antidepressant drugs on the excitability of human motor cortex: a study with paired magnetic stimulation on depressed patients

The effect of various drugs was investigated by using transcranial magnetic stimulation (TMS) both in healthy subjects and patients, and the results indicated an influence of antidepressant drugs (ADs) on motor excitability

DRD4 48bp multiallelic variants as age-population-specific biomarkers in Attention-Deficit/Hyperactivity Disorder

The identification of biomarkers to support the diagnosis and prediction of treatment response for attention-deficit/hyperactivity disorder (ADHD) is still a challenge. Our previous works highlighted the DRD4 (dopamine receptor D4) as the best potential genetic marker for childhood diagnosis and methylphenidate (MPH) response. Here, we aimed to provide additional evidence on biomarkers for ADHD diagnosis and treatment response, by using more specific approaches such as meta-analytic and bioinformatics tools. Via meta-analytic approaches including over 3000 cases and 16,000 controls, we demonstrated that, among the different variants studied in DRD4 gene, the 48-base pair, Variable Tandem Repeat Polymorphism, VNTR in exon 3 showed an age/population-specificity and an allelic heterogeneity. In particular, the 7R/“long” allele was identified as an ADHD risk factor in European-Caucasian populations (d = 1.31, 95%CI: 1.17–1.47, Z = 4.70/d = 1.36, 95%CI: 1.20–1.55, Z = 4.78, respectively), also, from the results of last meta-analysis, linked to the poor MPH efficacy. The 4R/“short” allele was a protective factor in European-Caucasian and South American populations (d = 0.83, 95%CI: 0.75–0.92, Z = 3.58), and was also associated to positive MPH response. These results refer to children with ADHD. No evidence of such associations was detected for adults with persistent ADHD (data from the last meta-analysis). Moreover, we found evidence that the 4R allele leads to higher receptor expression and increased sensitivity to dopamine, as compared with the 7R allele (d = 1.20, 95%CI: 0.71–1.69, Z = 4.81), and this is consistent with the ADHD protection/susceptibility effects of the respective alleles. Using bioinformatics tools, based on the latest genome-wide association (GWAS) meta-analysis of the Psychiatry Genomic Consortium (PGC), we demonstrated that the 48 bp VNTR is not in Linkage Disequilibrium with the DRD4 SNPs (Single Nucleotide Polymorphisms), which were not found to be associated with ADHD. Moreover, a DRD4 expression down regulation was found in ADHD specific brain regions (Putamen, Z score = −3.02, P = 0.00252). Overall, our results suggest that DRD4 48 bp VNTR variants should be considered as biomarkers to support the diagnosis of ADHD and to predict MPH response, although the accuracy of such a biomarker remains to be further elucidated