Pathologically mislocalised TDP-43 in upper motor neurons causes a die-forward spread of ALS-like pathogenic changes throughout the mouse corticomotor system.

Alterations in upper motor neuron excitability are one of the earliest phenomena clinically detected in ALS, and in 97 % of cases, the RNA/DNA binding protein, TDP-43, is mislocalised in upper and lower motor neurons. While these are two major pathological hallmarks in disease, our understanding of where disease pathology begins, and how it spreads through the corticomotor system, is incomplete. This project used a model where mislocalised TDP-43 was expressed in the motor cortex, to determine if localised cortical pathology could result in widespread corticomotor system degeneration. Mislocalised TDP-43 caused layer V excitatory neurons in the motor cortex to become hyperexcitable after 20 days of expression. Following cortical hyperexcitability, a spread of pathogenic changes through the corticomotor system was observed. By 30 days expression, there was a significant decrease in lower motor neuron number in the lumbar spinal cord. However, cell loss occurred selectively, with a significant loss in lumbar regions 1-3, and not lumbar regions 4-6. This regional vulnerability was associated with alterations in pre-synaptic excitatory and inhibitory proteins. Excitatory inputs (VGluT2) were increased in all lumbar regions, while inhibitory inputs (GAD65/67) were increased in lumbar regions 4-6 only. This data indicates that mislocalised TDP-43 in upper motor neurons can cause lower motor neuron degeneration. Furthermore, cortical pathology increased excitatory inputs to the spinal cord, to which local circuitry compensated with an upregulation of inhibition. These findings reveal how TDP-43 mediated pathology may spread through corticofugal tracts in ALS and identify a potential pathway for therapeutic intervention.

Estrogen Enhances Dendrite Spine Function and Recovers Deficits in Neuroplasticity in the prpTDP-43A315T Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) attacks the corticomotor system, with motor cortex function affected early in disease. Younger females have a lower relative risk of succumbing to ALS than males and older females, implicating a role for female sex hormones in disease progression. However, the mechanisms driving this dimorphic incidence are still largely unknown. We endeavoured to determine if estrogen mitigates disease progression and pathogenesis, focussing upon the dendritic spine as a site of action. Using two-photon live imaging we identify, in the prpTDP-43A315T mouse model of ALS, that dendritic spines in the male motor cortex have a reduced capacity for remodelling than their wild-type controls. In contrast, females show higher capacity for remodelling, with peak plasticity corresponding to highest estrogen levels during the estrous cycle. Estrogen manipulation through ovariectomies and estrogen replacement with 17ß estradiol in vivo was found to significantly alter spine density and mitigate disease severity. Collectively, these findings reveal that synpatic plasticity is reduced in ALS, which can be amelioriated with estrogen, in conjuction with improved disease outcomes.

Mislocalisation of TDP-43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex.

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease pathologically characterised by mislocalisation of the RNA-binding protein TAR-DNA-binding protein 43 (TDP-43) from the nucleus to the cytoplasm. Changes to neuronal excitability and synapse dysfunction in the motor cortex are early pathological changes occurring in people with ALS and mouse models of disease. To investigate the effect of mislocalised TDP-43 on the function of motor cortex neurons we utilised mouse models that express either human wild-type (TDP-43WT ) or nuclear localisation sequence-deficient TDP-43 (TDP-43ΔNLS ) on an inducible promoter that enriches expression to forebrain neurons. Pathophysiology was investigated through immunohistochemistry and whole-cell patch-clamp electrophysiology. Thirty days expression of TDP-43ΔNLS in adult mice did not cause any changes in the number of CTIP2-positive neurons in the motor cortex. However, at this time-point, the expression of TDP-43ΔNLS drives intrinsic hyperexcitability in layer V excitatory neurons of the motor cortex. This hyperexcitability occurs concomitantly with a decrease in excitatory synaptic input to these cells and fluctuations in both directions of ionotropic glutamate receptors. This pathophysiology is not present with TDP-43WT expression, demonstrating that the localisation of TDP-43 to the cytoplasm is crucial for the altered excitability phenotype. This study has important implications for the mechanisms of toxicity of one of the most notorious proteins linked to ALS, TDP-43. We provide the first evidence that TDP-43 mislocalisation causes aberrant synaptic function and a hyperexcitability phenotype in the motor cortex, linking some of the earliest dysfunctions to arise in people with ALS to mislocalisation of TDP-43.

Clinical and personality characteristics of adolescents with anorexia nervosa with or without non-suicidal self-injurious behavior.

PURPOSE: About one-fifth of patients with anorexia nervosa (AN) engage in non-suicidal self-injury (NSSI). This study examined clinical and temperament profile of female adolescents with both disorders (AN+NSSI) as compared with peers with AN only. METHODS: A consecutive sample of 73 female adolescents with AN (mean age: 13.77 years), who had been admitted to inpatient or day-hospital services, received clinical, cognitive, and temperament/character evaluations. Of them, 32 met DSM-5 criteria also for NSSI. Assessments included demographics, standard nutrition parameters, Youth Self-Report (YSR), Wechsler Intelligence Scale for Children IV (WISC-IV), Temperament and Character Inventory (TCI), and Global Assessment of Functioning (GAF). RESULTS: No differences were detected between AN+NSSI and AN in demographics, body mass index, or age at onset of AN. AN+NSSI had higher rate of binging and purging, higher YSR scores for both internalizing and externalizing psychopathology, lower total IQ, and lower Self-directedness and Cooperativeness scores. CONCLUSIONS: These data suggest that adolescents with AN+NSSI have psychopathological, cognitive and overall character features that differ from patients with AN only. These characteristics may have implications for treatment and outcome.

Viral priming of cell intrinsic innate antiviral signaling by the unfolded protein response.

The innate response to a pathogen is critical in determining the outcome of the infection. However, the interplay of different cellular responses that are activated following viral infection and their contribution to innate antiviral signalling has not been clearly established. This work shows that flaviviruses, including Dengue, Zika, West Nile and Tick-borne encephalitis viruses, activate the unfolded protein response before transcription of interferon regulatory factor 3 induced genes. Infection in conditions of unfolded protein response priming leads to early activation of innate antiviral responses and cell intrinsic inhibition of viral replication, which is interferon regulatory factor 3 dependent. These results demonstrate that the unfolded protein response is not only a physiological reaction of the cell to viral infection, but also synergizes with pattern recognition sensing to mount a potent antiviral response.

The evidence-based choice for antipsychotics in children and adolescents should be guaranteed.

PURPOSE: Drug use in the pediatric population still often features off-label prescriptions, particularly for psychotropic drugs. We reviewed the registration status, scientific evidence, and recommendations from the guidelines for antipsychotics used for psychiatric disorders in children. METHODS: Antipsychotic drugs marketed in Italy, the United Kingdom (UK) and United States (US) were identified with the ATC Classification System. The licensing status and Summary of Product Characteristics (SPC) were taken from the national formularies. We analyzed reviews and guidelines on antipsychotics use in children and adolescents in the MEDLINE, EMBASE, and PsycINFO databases. RESULTS: Out of 67 drugs, 19 were marketed with a pediatric license in at least one country: three in all the selected countries, and only paliperidone with the same indications. Haloperidol was the only antipsychotic authorized for autism in Italy and the UK, and as well as risperidone and aripiprazole in the US. Aripiprazole and paliperidone were licensed in all three countries for schizophrenia. Aripiprazole was licensed for bipolar disorders in all three countries. Haloperidol was licensed for Tourette syndrome in Italy and the UK, and pimozide and aripiprazole in the US. We retrieved 21 pertinent reviews and 13 guidelines for the management of neuropsychiatric disorders in pediatrics. There was a complete overlap between the authorized therapeutic indications and the available scientific evidence for autism in the US, for conduct disorders and bipolar disorders in the UK, and for Tourette syndrome and tics in the UK and Italy. CONCLUSIONS: These results highlight the different regulatory processes that deny to many children and adolescents the most appropriate and rational antipsychotic therapy.

ADHD prevalence estimates in Italian children and adolescents: a methodological issue.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is recognized as the most common, and most studied, developmental age disorder. Basic information, such as the most appropriate case definition and the best way to evaluate the disorder's prevalence rate, however, remains an open issue. METHODS: A comprehensive meta-analysis on the epidemiology of ADHD in Italy, which was lacking from the literature, was therefore performed to attempt to estimate the actual prevalence rate of ADHD, highlighting conceptual and quantitative differences between clinical-diagnosis and survey-based symptoms studies. The Medline, Embase, and PsycINFO databases, and the grey literature, were searched up to January 2018. The review was laid out in three main sections: an overall prevalence estimate, an epidemiological profile of ADHD symptoms, and an attempt to define the actual rate of ADHD diagnosis, as emerged from Italian studies. RESULTS: A total of 15 unique studies were included. These contributed to estimating the prevalence of ADHD in 67,838 subjects aged 5-17, representing 9 of the 20 regions (45%) of Italy. Overall, the pooled prevalence of ADHD was 2.9% (range: 1.1-16.7%). When distinguishing studies based on case definition, however, we found an average prevalence estimate, based on symptoms criteria, of 5.9% (range: 1.4 to 16.7%) and a best-estimate prevalence rate of 1.4% (range: 1.1 to 3.1%). CONCLUSIONS: Following the case definition for epidemiological studies of ADHD, counting only subjects with an ADHD diagnosis performed and confirmed by clinical assessment would reduce the wide variability in prevalence estimates, and, above all, would both describe the real rate of subjects suffering from ADHD disorder and avoid misdiagnosis.

Age level vs grade level for the diagnosis of ADHD and neurodevelopmental disorders.

A number of worldwide studies have demonstrated that children born later in the school year are more likely to receive an ADHD diagnosis than their same school-year peers. There is, however, variation in findings between countries. We aimed to confirm whether relative age is associated with ADHD diagnosis, with or without comorbidities, and to investigate whether relative age is associated with ADHD type and severity, and if this age relationship is in common with other neurodevelopmental disorder. We used the Lombardy Region's ADHD registry. Data on children aged 6 years and older from September 1, 2011 to December 31, 2017 were considered. We calculated incidence ratios to assess the inter-relations between relative age within the school year, using age at diagnosis of ADHD or of other psychiatric disorder, year of diagnosis, and total number of children born in Lombardy during the corresponding timeframe. Data on ADHD type, severity of diagnosed disorder clinical global impressions-severity scale, and repetition of a school-grade were also considered. 4081 children, 2856 of whom with ADHD, were identified. We confirmed that the cumulative incidence of ADHD diagnosis was greatest for younger children, in particular for boys, for whom the prevalence is greater. The relative age effect was not accounted for by ADHD comorbid disorders, ADHD of combined type or severity. The relative age effect was also observed for children with other neurodevelopmental disorders (without ADHD), with a similar profile as ADHD children: the incidence ratio was 1.78 (95% CI 1.07-2.97; p < 0.0247) for boys diagnosed before age ten. The findings have a potential implication for diagnostic and therapeutic practice, educational advice, and policies, besides to better plan and organize service systems and appropriately inform parents, children, and citizens.

Transition to Adult Mental Health Services for Young People With ADHD.

OBJECTIVE: To investigate the care management and continuity from child to adult mental health service for young adults with ADHD. METHOD: A questionnaire survey from 18 Regional ADHD Pediatric Centers (RAPC) in Lombardy, Italy, was used to collect data on transition protocols and population served, and to track the pathway of care of ADHD patients once they reached adulthood. RESULTS: Twenty-eight percent of RAPC had transition protocols and 3% of the population annually served were potential referrals to adult service. Of 52 patients who turned 18 years, just over 70% were monitored by the general practitioner, of those 5 with RAPC support. One fifth of patients continued to use mental health services, the majority was still monitored by the RAPC, and only three by services for adult. CONCLUSION: Managing the process of transition to adult services in mental health care remains a need to be prioritized and better defined for ADHD patients.

A Regional ADHD Center-Based Network Project for the Diagnosis and Treatment of Children and Adolescents With ADHD.

OBJECTIVE: We aimed to define the sociodemographic, clinical, and prescription profiles of the participants enrolled in the Italian Lombardy ADHD Register. METHOD: Data on patients evaluated by the 18 regional ADHD reference centers in the 2012 to 2013 period were analyzed. RESULTS: Seven hundred fifty-three of 1,150 (65%) suspected patients received a diagnosis of ADHD. In 24% of cases, there was a family history of ADHD. Four hundred eighty-three (64%) patients had at least one psychopathological disorder, the more common of which were learning disorders (35%). Eighty-four percent of patients received a prescription for psychoeducational interventions, 2% received only pharmacological treatment, and 14% a combination of both. Compared with patients treated with psychoeducational intervention alone, patients with drug prescriptions more commonly presented values of Clinical Global Impressions - Severity scale (CGI-S) of 5 or higher ( p < .0001). CONCLUSION: A continuous and systematic monitoring of patterns of care is essential in promoting significant improvements in clinical practice and ensuring an efficient and homogeneous quality of care.

Italian regional health service costs for diagnosis and 1-year treatment of ADHD in children and adolescents.

The main aim of this study was to estimate the costs associated with diagnostic assessment and 1-year therapy in children and adolescents enrolled in 18 ADHD reference centres. Data concerning 1887 children and adolescents from the mandatory ADHD registry database during the 2012-2014 period were analysed. The overall diagnostic and treatment costs per patient amounts to €574 and €830, respectively. The ADHD centre, the school as sender, and the time to diagnosis constitute cost drivers. Non-pharmacological therapy resulted as being more expensive for patients concomitantly treated with drugs (€929) compared to those treated with psychological interventions alone (€590; p = 0.006). This study gives the first and reliable estimate of the costs associated with both diagnosis and treatment of ADHD in Italy. Although costs associated with mental disorders are difficult to estimate, continuing efforts are need to define costs and resources to guarantee appropriate care, also for ADHD.

Comorbidity prevalence and treatment outcome in children and adolescents with ADHD.

Although ADHD comorbidity has been widely studied, some issues remain unsolved. This multicenter observational study aims to examine comorbid psychiatric disorders in a clinical sample of newly diagnosed, treatment naïve children and adolescents with and without ADHD and, to compare treatment efficacy based on the type of comorbidity. We performed an analysis of the medical records of patients identified from the Regional ADHD Registry database, enrolled in 18 ADHD centers in the 2011-2016 period. 1919 of 2861 subjects evaluated (67%) met the diagnostic criteria for ADHD: 650 (34%) had only ADHD, while 1269 (66%) had at least one comorbid psychiatric disorder (learning disorders, 56%; sleep disorders, 23%; oppositional defiant disorder, 20%; anxiety disorders, 12%). Patients with ADHD of combined type and with severe impairment (CGI-S ≥5) were more likely to present comorbidity. 382 of 724 (53%) followed up patients improved after 1 year of treatment. ADHD with comorbidity showed greater improvement when treated with combined interventions or methylphenidate alone. Specifically, combined treatment showed significant superiority for ADHD with learning disorders (ES 0.66) and ODD (ES 0.98), lower for ADHD with sleep or anxiety disorders. Training intervention alone showed only medium efficacy (ES 0.50) for ADHD and learning disorders. This study was the first describing comorbidity patterns of ADHD in Italy, confirming, in a multicenter clinical setting, that ADHD is more often a complex disorder. Findings highlight important diagnostic, therapeutic, and service organization aspects that should be broadly extended to ensure an appropriate and homogenous ADHD management.

The impact of a model-based clinical regional registry for attention-deficit hyperactivity disorder.

This article describes the development and clinical impact of the Italian Regional ADHD Registry, aimed at collecting and monitoring diagnostic and therapeutic pathways of care for attention-deficit hyperactivity disorder children and adolescents, launched by the Italian Lombardy Region in June 2011. In particular, the model-based software used to run the registry and manage clinical care data acquisition and monitoring, is described. This software was developed using the PROSAFE programme, which is already used for data collection in many Italian intensive care units, as a stand-alone interface case report form. The use of the attention-deficit hyperactivity disorder regional registry led to an increase in the appropriateness of the clinical management of all patients included in the registry, proving to be an important instrument in ensuring an appropriate healthcare strategy for children and adolescents with attention-deficit/hyperactivity disorder.

Transition to adult mental health services for young people with attention deficit hyperactivity disorder in Italy: Parents' and clinicians' experiences.

OBJECTIVE: The aim of this study was to describe the experiences of parents and clinicians in relation to the transition from child and adolescent neuropsychiatric services (CANPS) to adult services for people with attention deficit hyperactivity disorder (ADHD) in Italy. METHODS: Parents of people with ADHD who reached the transition boundary for CANPS were sampled from the A.I.F.A. association (Italian Association of ADHD Families). We thematically analyzed informative and qualitative questionnaires completed by parents and clinicians. RESULTS: Parents' (n = 24) and clinicians' (n = 27) experiences differed slightly on challenges and unmet needs, whereas clinicians agreed on the variables required for an optimal transition process. Poor transition and multiple barriers to such care were identified. Specifically, far fewer people received services, especially public health services, after reaching the age of 18, and perceived barriers included problems with user access, limited transition protocols, poor service coordination, and possible lack of ADHD-related knowledge on the part of adult practitioners. CONCLUSIONS: Care continuity in mental healthcare remains a need to be prioritized and better defined also for ADHD patients (and their parents). Parents' and clinicians' experiences are more likely to be positive if transition management is characterized by a gradual preparation, a period of parallel care, and commonly acknowledged, clear information on available services and how to access them. Identifying the needs and barriers of the people representing the different roles (clinicians, parents, and users) involved in the transition to adult mental health services is of particular importance in designing effective, shared transfer planning procedures.

Guanfacine for attention deficit and hyperactivity disorder in pediatrics: a systematic review and meta-analysis.

To review the evidence from randomized controlled trials (RCTs) on the safety and efficacy of guanfacine in pediatric attention deficit hyperactivity disorder (ADHD), a bibliographic search up to May 2014 was performed using the Cochrane Library׳s Central Register of Controlled Trials, the Embase, PsycINFO, and Medline databases, and clinical trials registers. The search terms used were: ["guanfacine"] and ["child" or "adolescent" or "pediatrics"] and ["randomized controlled trial"] and ["Attention Deficit Disorder with Hyperactivity" or "Attention Deficit Disorder" or "Attention Hyperactivity Disorder" or "Hyperactivity" or "ADHD"]. A meta-analysis was performed using response, defined as a score ≤ 2 on the Clinical Global Impression Improvement score, as the outcome measure. In all, 7 out of 48 studies were included, for a total of 1752 participants. All studies compared guanfacine versus placebo, with a duration ranging from 6 to 16 weeks. In all, the Clinical Global Impression Improvement score was reported as a secondary measure. Overall, 694/1177 (59.0%) participants in the guanfacine group benefited from the treatment compared to 192/575 (33.3%) in the placebo group (pooled OR 3.2; 95%CI 2.4-4.1). The participants with at least one adverse event were 948 (82.4%) in the guanfacine and 376 (67.9%) in the placebo group (OR 2.6; 95%CI 1.6-4.4). Somnolence (OR 4.9), sedation (OR 2.8), and fatigue (OR 2.2), were the adverse events with the greatest risk of occurrence in the guanfacine versus the placebo group. On the basis of seven randomized, placebo controlled trials guanfacine resulted safe and effective in treating children and adolescents with ADHD.

Mood symptoms in children and adolescents with autism spectrum disorders.

Asperger Syndrome (AS) and High Functioning Autism (HFA) are psychiatric conditions belonging to the Autistic Spectrum Disorders (ASDs), characterized by social dysfunction and focused interest, in the absence of mental retardation. Previous reports suggest that AS/HFA may be associated with important psychiatric comorbidities. Among the psychiatric internalizing disorders, depression and anxiety are probably the most common disorders. The aim of this study is to evaluate the prevalence of mood disorders and identifying peculiar clinical features in subjects suffering from AS and HFA. 30 male patients with AS/HFA, 30 male patients affected by Major Depression (MD) and 35 male Typically Developing (TD) comparison were assessed with the CDI and the CDRS-R. Participants' parents were invited to complete the CBCL and the P-YMRS. Moreover, the CGAS was rated by the clinicians. The evaluation of depressive symptoms showed that AS/HFA group reported higher depressive symptoms, as showed by CDI total, CBCL internalizing and CDRS-R total, compared to the TD group. No significant difference of depressive symptoms was found between the AS/HFA and the MD group, with the exception of CDRS-R total score. Moreover, linear regression analysis in the AS/HFA group between CGAS and depressive symptoms revealed that a higher level of depressive symptoms increased the risk of poorer global functioning. These results suggest that the depressive symptoms in AS/HFA patients may be associated with poorer global functioning, with a consequent impairment in their psychological profile and social adjustment, and should alert clinicians to the importance of assessing mood disorders in order to choose the appropriate treatment.

Self-esteem evaluation in children and adolescents suffering from ADHD.

BACKGROUND: Several recent studies investigated the relationship between self-esteem and ADHD, however, the results are still controversial. In the present study we analyze the characteristics of self-esteem in a sample of children and adolescents suffering from ADHD, with a particular focus on the relationship between ADHD symptoms severity and treatment strategies. METHODS: A total of 85 patients with ADHD (44 drug-free and 41 drug-treated, 23 of which atomoxetine-treated and 18 Methylphenidate-treated) and 26 healthy controls were enrolled in the study in order to evaluate self-esteem using the Self-esteem Multidimensional Test (TMA). RESULTS: ADHD subjects revealed lower scores on all self-esteem domains compared to controls. Both ADHD drug-free (47.1%) and ADHD drug-treated (44.1%) groups showed significantly higher rates of subjects in the pathological range as compared to normal control group (8.8%) (p <.001) with a higher percentage of subjects in the pathological range. Among ADHD drug-treated subjects, the methylphenidate group showed higher self-esteem scores as compared to the atomoxetine group. CONCLUSION: A lower self-esteem profile is more common in subjects suffering from ADHD than in healthy controls, suggesting the importance of an early detection of psychological well-being in these children in order to reduce the ADHD symptoms long-term impacts.

Psychiatric comorbidities in asperger syndrome and high functioning autism: diagnostic challenges.

Several psychiatric conditions, both internalizing and externalizing, have been documented in comorbidity with Asperger Syndrome (AS) and High Functioning Autism (HFA). In this review we examine the interplay between psychiatric comorbidities and AS/HFA. In particular, we will focus our attention on three main issues. First, we examine which psychiatric disorders are more frequently associated with AS/HFA. Second, we review which diagnostic tools are currently available for clinicians to investigate and diagnose the associated psychiatric disorders in individuals with AS/HFA. Third, we discuss the challenges that clinicians and researchers face in trying to determine whether the psychiatric symptoms are phenotypic manifestations of AS/HFA or rather they are the expression of a distinct, though comorbid, disorder. We will also consider the role played by the environment in the manifestation and interpretation of these symptoms. Finally, we will propose some strategies to try to address these issues, and we will discuss therapeutic implications.