Digital therapeutics in neurology.

Digital therapeutics (DTx) is a section of digital health defined by the DTx Alliance as "delivering evidence-based therapeutic interventions to patients that are driven by software to prevent, manage, or treat a medical disorder or disease. They are used independently or in concert with medications, devices, or other therapies to optimize patient care and health outcomes". Chronic disabling diseases could greatly benefit from DTx. In this narrative review, we provide an overview of DTx in the care of patients with neurological dysfunctions.

Acute environmental temperature variation affects brain protein expression, anxiety and explorative behaviour in adult zebrafish.

This study investigated the effect of 4-d acute thermal treatments at 18 °C, 26 °C (control) and 34 °C on the nervous system of adult zebrafish (Danio rerio) using a multidisciplinary approach based on behavioural tests and brain proteomic analysis. The behavioural variations induced by thermal treatment were investigated using five different tests, the novel tank diving, light and dark preference, social preference, mirror biting, and Y-Maze tests, which are standard paradigms specifically tailored for zebrafish to assess their anxiety-like behaviour, boldness, social preference, aggressiveness, and explorative behaviour, respectively. Proteomic data revealed that several proteins involved in energy metabolism, messenger RNA translation, protein synthesis, folding and degradation, cytoskeleton organisation and synaptic vesiculation are regulated differently at extreme temperatures. The results showed that anxiety-like behaviours increase in zebrafish at 18 °C compared to those at 26 °C or 34 °C, whereas anxiety-related protein signalling pathways are downregulated. Moreover, treatments at both 18 °C and 34 °C affect the exploratory behaviour that appears not to be modulated by past experiences, suggesting the impairment of fish cognitive abilities. This study is the continuation of our previous work on the effect of 21-d chronic treatment at the same constant temperature level and will enable the comparison of acute and chronic treatment effects on the nervous system function in adult zebrafish.

Lifestyle and Mediterranean diet adherence in a cohort of Southern Italian patients with Multiple Sclerosis.

BACKGROUND/OBJECTIVES: Several studies supported the beneficial effects of the Mediterranean diet (MeDi) on chronic diseases. In Multiple Sclerosis (MS), the MeDi might interfere with systemic inflammatory state, gut microbiota, and comorbidities. The Med Diet Score (MDS) estimates the adherence to the MeDi and the cardiovascular (CV) risk. Aims of our study were i) to photograph lifestyle and diet habits of a southern Italy cohort of people with MS (pwMS), and ii) to investigate the impact of the MeDi on MS clinical outcomes. SUBJECTS/METHODS: We conducted a multi-center, cross-sectional study, enrolling 435 consecutive consenting pwMS, attending the outpatient clinics for routine follow-up visits. Participants underwent a clinical examination and a 29-item self-administered questionnaire on life and dietary habits. Disease phenotype, Expanded Disability Status Scale (EDSS), MS Severity Score (MSSS), waist circumference (WC), Body Mass Index (BMI), therapies, and comorbidities, were updated. MDS was assessed and correlated with current and retrospective clinical data. RESULTS: 75.8% of respondents were interested in nutrition, 72.8% were non-smokers, 52.9% performed physical activity, and 45.6% used food supplements. MDS was higher in pwMS with normal WC (p = 0.031), and inversely correlated with MSSS (p = 0.013) and EDSS (p = 0.012) at survey time. MDS did not correlate with the total number of relapses (before and after diagnosis) (p = 0.372). Metabolic comorbidities were associated with an increased 10-year CV risk (r = 0.85, p = 0.002). CONCLUSION: Our findings suggest a putative beneficial effect of the MeDi on WC, MS course and disability. Given the role of chronic systemic inflammation in maintenance of autoimmunity and secondary neurodegeneration, both involved in long-term disability, we may suppose a beneficial effect of the MeDi on MS long-term disability outcomes, probably mediated by a modulation of the gut microbiota and the low-grade chronic systemic inflammation.

Predictors of fatigue severity in early, de novo Parkinson disease patients: A 1-year longitudinal study.

INTRODUCTION: Fatigue is one of the most common and disabling nonmotor symptom in Parkinson's disease (PD). The aim of the present study was to investigate the 1-year course of fatigue in a consecutive sample of de novo drug-naïve patients with PD, and at systematically searching for baseline motor and nonmotor predictors associated with fatigue severity over time. METHODS: Fifty-five consecutive de novo PD patients (age: 64.71 ± 7.74 years) underwent a comprehensive examination, including Parkinson Fatigue Scale, Epworth Sleepiness Scale, Parkinson's Disease Sleep Scale, Beck Depression Inventory, Parkinson's Anxiety Scale, Apathy Evaluation Scale, and an extensive neuropsychological evaluation. Bivariate and multiple regression analyses were performed to identify baseline predictors independently related to fatigue severity at 1-year follow-up. RESULTS: Prevalence rate of fatigue (defined by PFS cut-off) increased from 22% at baseline to 38% at 1-year follow-up. A similar increase in prevalence was observed for excessive daytime sleepiness, and apathy. Among patients with fatigue at baseline, 91% had fatigue at follow-up too (i.e., persistent fatigue). Multivariate regression analysis identified fatigue (p < 0.01), daytime sleepiness (p < 0.01), and emotional apathy (p < 0.01) as the main baseline variables significantly predicting fatigue severity at 1-year follow-up. CONCLUSION: In early PD, fatigue increases and persists over time, and its severity is related to higher baseline levels of fatigue, excessive daytime sleepiness, and emotional apathy. These results warrant to monitor fatigue since the early stage of disease, and suggest that treating excessive daytime sleepiness and emotional apathy might prevent its worsening.

Environmental temperature variation affects brain protein expression and cognitive abilities in adult zebrafish (Danio rerio): A proteomic and behavioural study.

Water temperature is an important environmental parameter influencing the distribution and the health of fishes and it plays a central role in ectothermic animals. The aim of this study is to determine the effects of environmental temperature on the brain proteome and the behavioural responses in zebrafish, a widely used animal model for environmental "omics" studies. Adult specimens of wild-type zebrafish were kept at 18 °C, 34 °C and 26 °C (control) for 21 days. Proteomic data revealed that several proteins involved in cytoskeletal organization, mitochondrial regulation and energy metabolism are differently regulated at the extreme temperatures. In particular, the expression of proteins associated to synapses and neurotransmitter release is down-regulated at 18 °C and 34 °C. In both thermal conditions, fish exhibited a reduced interest for the novel environment and an impairment of cognitive abilities during Y-Maze behavioural tests. The observed pathways of protein expression are possibly associated to functional alterations of the synaptic transmission that may result in cognitive functions impairment at central nervous system level as those revealed by behavioural tests. This study indicates that temperature variations can elicit biochemical changes that may affect fish health and behaviour. This combined approach provides insights into mechanisms supporting thermal acclimation and plasticity in fishes. SIGNIFICANCE: Environmental temperature variation may impact on all levels of biological life. Understanding the impact of thermal variation on the nervous system and animal behaviour is of primary importance since the results obtained can be applied from the ecological to the biomedical fields.

Fatigue in Parkinson's disease: Italian validation of the Parkinson Fatigue Scale and the Fatigue Severity Scale using a Rasch analysis approach.

INTRODUCTION: The Fatigue Severity Scale (FSS-9) and the Parkinson Fatigue Scale (PFS-16) are commonly used for assessing fatigue in Parkinson's disease (PD). Here we validated the Italian version of these scales, assessed their psychometric properties by Rasch analysis, and computed their optimal cut-off scores using clinical diagnosis of PD-related fatigue as the gold standard. METHODS: PD patients (n = 167) completed the Italian versions of FSS-9 and PFS-16. Each item of PFS-16 was scored both on a 5-point (PFS-16polytomous) and on a 2-point scale (PFS-16dichotomous). RESULTS: All scales showed an adequate overall Rasch model fit, high reliability, and good discriminant, convergent, and concurrent validity, but were less accurate in measuring very high and very low fatigue levels. No evidence of differential item functioning with respect to age, sex, and severity of parkinsonian symptoms was found. Some items of FSS-9 (item 1), PFS-16polytomous (items 1 and 13), and PFS-16dichotomous (items 1, 8, and 13) showed misfit, possibly due to their content concerning sleep and motivation disorders. When FSS-9 and PFS-16polytomous' responses were rescored on a 3-point scale, the discriminability across response categories improved. The optimal cut-off score in detecting clinically-diagnosed fatigue (observed in 20% of the sample) was 3.09 for PFS-16polytomous, 8.00 for PFS-16dichotomous, and 4.67 for FSS-9. CONCLUSIONS: The Italian version of PFS-16 and FSS-9 showed sound psychometric properties and can be confidently used to quantify fatigue symptoms in PD, although clinical diagnosis of fatigue should rely on validated criteria. The PFS-16polytomous exhibited advantages with respect to PFS-16dichotomous.

Factors interfering with parenthood decision-making in an Italian sample of people with multiple sclerosis: an exploratory online survey.

BACKGROUND: Little is known about the influence of multiple sclerosis (MS) diagnosis on parenthood attitude in people with MS (pwMS). OBJECTIVE: To investigate the impact of diagnosis, clinical features and external disease-related influences on parenthood decision-making in Italian pwMS. METHODS: A web-based survey was posted on SMsocialnetwork.com to investigate clinical status, parenthood desire, influences on family planning, pregnancy outcomes, abortions and adoptions of pwMS. RESULTS: 33/395 respondents never wanted to become parent because of MS ("anti-parenthood after diagnosis"). 362 declared to be in favor of parenthood. 51% pwMS having a child by the survey time had already received the MS diagnosis at first childbirth. The frequency of a second child in pwMS after diagnosis was 38% compared to 67% in people without yet MS diagnosis. 16% of pwMS were discouraged to become parent after diagnosis, mainly by medical personnel. In 71% of respondents, diagnosis did not delay the decision to become parent and only 39% were counseled by treating physician to plan pregnancy. Patients' distribution according to the clinical phenotype (exclusively relapsing vs exclusively progressive) showed a higher proportion of progressive patients in the "anti-parenthood after diagnosis" subgroup. CONCLUSION: MS diagnosis impacted dramatically on the life project of 7% of pwMS that decided not to have children because of the disease and in pro-parenthood pwMS impacted especially on having the second child. Only a minority was counseled to plan pregnancy. A worse disease course driving to a progressive phenotype at survey time might have negatively impacted on parenthood desire.

Discontinuation of teriflunomide and dimethyl fumarate in a large Italian multicentre population: a 24-month real-world experience.

BACKGROUND: Teriflunomide (TRF) and Dimethyl fumarate (DMF) are licensed drugs for relapsing-remitting Multiple Sclerosis (RRMS). OBJECTIVES: We aimed to compare the rate and the time to discontinuation among persons with RRMS (pwRRMS), newly treated with TRF and DMF. MATERIALS AND METHODS: A retrospective study on prospectively collected data was performed in nine tertiary MS centers, in Italy. The 24-month discontinuation rate in the two cohorts was the primary study outcome. We also assessed the time to discontinuation and reasons of therapy withdrawn. Discontinuation of TRF and DMF was defined as a gap of treatment ≥ 60 days. RESULTS: A cohort of 903 pwRRMS (316 on TRF and 587 on DMF) was analyzed. During 24 months of follow-up, pwRRMS on TRF and DMF showed similar discontinuation rates. The analysis of predictors with Cox regression model showed differences between the two groups (p for log-rank test = 0.007); male gender [HR 2.21 (1.00-4.90); p = 0.01] and the number of previous switches [HR 1.47 (1.16-1.86); p = 0.01] were associated with higher hazard of discontinuation in the DMF group. CONCLUSIONS: In a real-world setting, pwRRMS on TRF and DMF had similar discontinuation rates over 24 months. Male pwRRMS on DMF with a previous history of therapeutic failure are at more risk of discontinuation therapy.

Proteolysis in septic shock patients: plasma peptidomic patterns are associated with mortality.

BACKGROUND: Uncontrolled proteolysis contributes to cell injury and organ dysfunction in animal models of circulatory shock. We investigated in humans the relationship between septic shock, proteolysis, and outcome. METHODS: Intensive care patients with septic shock (n=29) or sepsis (n=6) and non-hospitalised subjects (n=9) were recruited as part of the prospective observational trial 'ShockOmics' (ClinicalTrials.gov Identifier NCT02141607). A mass spectrometry-based approach was used to analyse the plasma peptidomes and the origin of circulating peptides from proteolysis in the enrolled subjects. RESULTS: Evidence of systemic proteolysis was indicated by a larger number of circulating peptides in septic shock patients, compared with septic patients and non-hospitalised healthy subjects. The peptide count and abundance in the septic shock patients were greater in patients who died (n=6) than in survivors (n=23), suggesting an association between magnitude of proteolysis and outcome. In silico analysis of the peptide sequences and of the sites of cleavage on the proteins of origin indicated a predominant role for serine proteases, such as chymotrypsin, and matrix metalloproteases in causing the observed proteolytic degradation. CONCLUSIONS: Systemic proteolysis is a novel fundamental pathological mechanism in septic shock. Plasma peptidomics is proposed as a new tool to monitor clinical trajectory in septic shock patients. CLINICAL TRIAL REGISTRATION: NCT02141607.

Fake news, influencers and health-related professional participation on the Web: A pilot study on a social-network of people with Multiple Sclerosis.

BACKGROUND: Over the last few decades, patients have increasingly been searching for health information on the Internet. This aspect of information seeking is important, especially for people affected by chronic pathologies and require lifelong treatment and management. These people are usually very well informed about the disease but are nonetheless vulnerable to hopes of being cured or saved, often amplified by misinformation, myths, legends, and therapies that are not always scientifically proven. Many studies suggest that some individuals prefer to rely on the Internet as their main source of information, often hindering the patient-doctor relationship. A professional approach is imperative to maintain confidentiality, honesty, and trust in the medical profession. OBJECTIVE: we aimed to examine, in a medically supervised Italian web community (SMsocialnetwotk.com) dedicated to people with Multiple Sclerosis (pwMS), the posts shared by users and to verify the reliability of contents of posts shared by users pinpointed as Influencers through an online questionnaire. METHODS: we grouped the posts published on SMsocialnetwork from April to June 2015 into those with medical content (scientifically correct or fake news), and those related to social interactions. Later, we gave a questionnaire to the community asking to identify the three users/Influencers providing the most reliable advice for everyday life with MS and the three users/Influencers providing the most useful information about MS treatments. RESULTS: 308 posts reported scientific and relevant medical information, whereas 72 posts included pieces of fake news. 1420 posts were of general interest. Four out of the 6 Influencers had written only posts with correct medical information (3 were pwMS, 1 was a Neurologist) and never any fake news. The remaining 2 appointed Influencers (2 pwMS) had written only posts about general interests. CONCLUSION: the identification of fake news and their authors has shown that the latter are never appointed as Influencers. SMsocialnetwork.com acted as a "web safe environment" where the Influencers contributed by sharing only correct medical information and never fake news. We speculate that the presence of neurologists and psychologists supervising the information flow might have contributed to reduce the risk of fake news spreading and to avoid their acquisition of authoritative meaning.

Motor, behavioural, and cognitive correlates of fatigue in early, de novo Parkinson disease patients.

INTRODUCTION: Fatigue is one of the most common and disabling non-motor symptoms in Parkinson's disease (PD). The objective of this study was to determine prevalence and motor, behavioural, and cognitive correlates of distressing fatigue in early, de novo PD patients. METHODS: Eighty-one consecutive de novo PD patients (64% men; mean age 65.73 ± 8.26 years) underwent a comprehensive examination, including Parkinson's disease Fatigue Scale (PFS), Epworth Sleepiness Scale (ESS), Parkinson's Disease Sleep Scale (PDSS), Beck Depression Inventory (BDI), Parkinson's Anxiety Scale (PAS), and Apathy Evaluation Scale (AES). Moreover, all patients underwent a detailed neuropsychological evaluation exploring attention and working memory, executive functions, memory, visuospatial abilities and language. Score of patients with or without distressing fatigue (defined as a PFS score ≥ 8) were compared by Student's t-test or Pearson's chi-square test. Logistic regression analyses were performed to search for motor and non-motor features independently associated with presence of distressing fatigue. RESULTS: Twelve (15%) patients presented distressing fatigue. Logistic regression identified sleepiness (p = 0.04), "episodic anxiety" subscale of PAS (p = 0.005), and "cognitive apathy" subscale of AES (p = 0.017) as the main factors associated with distressing fatigue. No significant association was found between diagnosis of Mild Cognitive Impairment and distressing fatigue (p = 0.745). CONCLUSION: In a sample of consecutive de novo PD patients, distressing fatigue is associated with episodic anxiety, cognitive apathy and sleepiness, but not with cognitive impairment. Our findings suggest possible shared pathogenic mechanisms underlying these non-motor symptoms and foster development of early combined therapeutic approaches.

The Italian Neuroimaging Network Initiative (INNI): enabling the use of advanced MRI techniques in patients with MS.

Magnetic resonance imaging (MRI) is an important paraclinical tool to diagnose and monitor multiple sclerosis (MS). Conventional MRI measures lack of pathological specificity and are weakly correlated with MS clinical manifestations. Advanced MRI techniques are improving the understanding of the mechanisms underlying tissue injury, repair, and functional adaptation in MS; however, they require careful standardization. The definition of standardized methods for the collection and analysis of advanced MRI techniques is central not only to improve the understanding of disease pathophysiology and evolution, but also to generate research hypotheses, monitor treatment, increase cost-effectiveness and power of clinical trials. We promoted the Italian Neuroimaging Network Initiative (INNI), involving centers and investigators with an International recognized expertise, with the major goal to determine and validate novel MRI biomarkers to be utilized as predictors and/or outcomes in future MS studies. The INNI initiative supported the creation of a centralized repository, where advanced structural and functional MRI scans available at the participating sites, with the related clinical and neuropsychological data, are collected. These data will be used to perform research studies to identify clinical, neuropsychological and imaging biomarkers characteristics of the entire spectrum of MS. INNI will be instrumental to help to define standardized MRI and clinical protocols towards an increasing uptake of personalized interventions for people with MS at a national and international level. Upon approval of the INNI Steering Committee, the data collected in the online database will be shared with any research center detailing specific research proposals on disease pathophysiology or treatment effects.

Neurobiological after-effects of non-invasive brain stimulation.

BACKGROUND: In recent years, many studies have evaluated the effects of noninvasive brain stimulation (NIBS) techniques for the treatment of several neurological and psychiatric disorders. Positive results led to approval of NIBS for some of these conditions by the Food and Drug Administration in the USA. The therapeutic effects of NIBS have been related to bi-directional changes in cortical excitability with the direction of change depending on the choice of stimulation protocol. Although after-effects are mostly short lived, complex neurobiological mechanisms related to changes in synaptic excitability bear the potential to further induce therapy-relevant lasting changes. OBJECTIVE: To review recent neurobiological findings obtained from in vitro and in vivo studies that highlight molecular and cellular mechanisms of short- and long-term changes of synaptic plasticity after NIBS. FINDINGS: Long-term potentiation (LTP) and depression (LTD) phenomena by itself are insufficient in explaining the early and long term changes taking place after short episodes of NIBS. Preliminary experimental studies indicate a complex scenario potentially relevant to the therapeutic effects of NIBS, including gene activation/regulation, de novo protein expression, morphological changes, changes in intrinsic firing properties and modified network properties resulting from changed inhibition, homeostatic processes and glial function. CONCLUSIONS: This review brings into focus the neurobiological mechanisms underlying long-term after-effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) recently obtained from in vitro and in vivo studies, both in animals and humans.

Default mode network changes in multiple sclerosis: a link between depression and cognitive impairment?

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), depression is a common disorder whose pathophysiology is still debated. To gain insights into the pathophysiology of depression in MS, resting-state (RS) functional connectivity (FC) changes of the default mode network (DMN), salience network (SN) and executive control network (ECN) were assessed in a group of depressed MS (D-MS) patients and in appropriately matched control groups. METHODS: Sixteen D-MS patients, 17 non-depressed MS (ND-MS) patients, 17 non-depressed healthy controls and 15 depressed subjects (D-S), age, sex and education matched, cognitively preserved and non-fatigued, were enrolled. All participants underwent a neuropsychological evaluation and RS functional magnetic resonance imaging study. RESULTS: Comparing D-MS patients with D-S, within the DMN, a significant RS-FC suppression was found in the posterior cingulate cortex (PCC); comparing D-MS with ND-MS, FC was significantly increased in the anterior cingulate cortex and significantly reduced in the PCC. Within the SN increased FC in the right supramarginal gyrus and right middle frontal gyrus was found in D-MS patients compared to D-S and to ND-MS; within the ECN increased FC in the right inferior parietal cortex was found in D-MS patients compared to ND-MS patients. CONCLUSIONS: In cognitively preserved D-MS patients, FC derangement occurs in the SN, ECN and DMN. In the latter, changes occurring both in the anterior cingulate cortex and PCC suggest that depression in MS may be linked to MS itself and, in particular, to a peculiar pattern of network abnormalities favored by MS pathology through disconnection mechanisms. Reduced FC in the PCC, similar to MS patients with cognitive impairment, suggests a functional link between depression and cognitive impairment in MS.

Anxiety in Multiple Sclerosis: psychometric properties of the State-Trait Anxiety Inventory.

OBJECTIVE: The aims of the present study were to examine psychometric properties of the Spielberger State-Trait Anxiety Inventory (STAI-Y-1 and STAI-Y-2, respectively) in a Multiple Sclerosis (MS) population and to identify a cut-off score to detect those MS patients with high level of state and/or trait anxiety who could be more vulnerable to development of depression and/or cognitive defects. MATERIAL AND METHODS: The STAI-Y-1 and STAI-Y-2 was completed by a group of patients (n = 175) affected by MS and a group of healthy subjects (n = 150) matched for age, educational level, and gender. In MS patients internal consistency, divergent and discriminant validities were evaluated. Construct validity was examined by exploratory factor analysis for each scale. RESULTS: There was no missing data, no floor or ceiling effects for both scales. The two scales showed high internal consistency, good divergent, and Known-groups validities. To identify high levels of state and trait anxiety in a patient with MS, we proposed three gender specific screening cut-off values (1, 1.5, 2 SD) for the STAI-Y-1 and the STAI-Y-2. CONCLUSIONS: The findings showed that the STAI-Y-1 and the STAI-Y-2 are a valid tool for clinical use in MS patients and can be useful to measure the severity of anxiety and to identify those patients with high anxiety to introduce them in specific non-pharmacological intervention.

Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1.

Mesenchymal stem cells (MSC) represent a promising therapeutic approach in many diseases in view of their potent immunomodulatory properties, which are only partially understood. Here, we show that the endothelium is a specific and key target of MSC during immunity and inflammation. In mice, MSC inhibit activation and proliferation of endothelial cells in remote inflamed lymph nodes (LNs), affect elongation and arborization of high endothelial venules (HEVs) and inhibit T-cell homing. The proteomic analysis of the MSC secretome identified the tissue inhibitor of metalloproteinase-1 (TIMP-1) as a potential effector molecule responsible for the anti-angiogenic properties of MSC. Both in vitro and in vivo, TIMP-1 activity is responsible for the anti-angiogenic effects of MSC, and increasing TIMP-1 concentrations delivered by an Adeno Associated Virus (AAV) vector recapitulates the effects of MSC transplantation on draining LNs. Thus, this study discovers a new and highly efficient general mechanism through which MSC tune down immunity and inflammation, identifies TIMP-1 as a novel biomarker of MSC-based therapy and opens the gate to new therapeutic approaches of inflammatory diseases.

Psychometric properties and validity of Beck Depression Inventory II in multiple sclerosis.

BACKGROUND AND PURPOSE: Depression is the most common psychiatric disorder in multiple sclerosis (MS). Self-report depression scales are frequently used as screening, diagnostic and grading instruments. This study investigated the psychometric properties of the Beck Depression Inventory second edition (BDI-II) for assessing depressive disorders in a sample of Italian MS patients. METHODS: The sample included 141 consecutive non-demented MS patients who completed the BDI-II and the Chicago Multiscale Depression Inventory (CMDI). MS patients also completed a clinical interview, a neurological/neuropsychological examination and a Fatigue Severity Score (FSS) questionnaire in order to assess divergent validity. RESULTS: The BDI-II showed good internal consistency (Cronbach's alpha 0.89) and good convergent and divergent validity. With respect to CMDI serving as the 'gold standard', the receiver operating characteristic curve revealed that BDI-II is an adequate diagnostic measure and that the optimum total cut-off score was 18.5. Such score identified clinically relevant depressive symptoms in 25.5% of our MS sample. CONCLUSIONS: The BDI-II is a simple, reliable and valid tool for detecting and grading depressive symptoms in Italian MS patients.

Regional cortical thinning in multiple sclerosis and its relation with cognitive impairment: A multicenter study.

OBJECTIVES: The objectives of this paper are to compare in a multicenter setting patterns of regional cortical thickness in patients with relapsing-remitting multiple sclerosis (RRMS) and cognitive impairment (CI) and those cognitively preserved (CP), and explore the relationship between cortical thinning and cognitive performance. METHODS: T1-weighted isotropic brain scans were collected at 3T from seven European centers in 60 RRMS patients and 65 healthy controls (HCs). Patients underwent clinical and neuropsychological examinations. Cortical thickness (CTh) measures were calculated using FreeSurfer (failing in four) and both lobar and vertex-based general linear model (GLM) analyses were compared between study groups. RESULTS: Twenty (36%) MS patients were classified as CI. Mean global CTh was smaller in RRMS patients compared to HCs (left 2.43 vs. 2.53 mm, right 2.44 vs. 2.54 mm, p < 0.001). Multivariate GLM regional analysis showed significantly more temporal thinning in CI compared to CP patients. Verbal memory scores correlated to regional cortical thinning in the insula whereas visual memory scores correlated to parietal thinning. CONCLUSIONS: This multicenter study showed mild global cortical thinning in RRMS. The extent of thinning is less pronounced than previously reported. Only subtle regional differences between CI and CP patients were observed, some of which related to specific cognitive domains.

Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). METHODS: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. RESULTS: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). CONCLUSIONS: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.

Psychopathological comorbidities in medication-overuse headache: a multicentre clinical study.

BACKGROUND AND PURPOSE: In medication-overuse headache (MOH) patients, the presence of psychopathological disturbances may be a predictor of relapse and poor response to treatment. This multicentre study aimed to assess the occurrence of psychopathological disorders in MOH patients by comparing the incidence of psychopathological disturbances with episodic migraine (EM) patients and healthy controls (HC). METHODS: The psychopathological assessment of patients and HC involved the administrations of the Beck Depression Inventory, the Beck Anxiety Inventory, the Modified Mini International Neuropsychiatric Interview (M-MINI), the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Leeds Dependence Questionnaire. RESULTS: The MOH, EM and HC groups (88, 129 and 102 subjects, respectively) differed significantly from each other for the presence of moderate/severe anxiety, whereas mood disorder and depression were revealed in similar proportions for both MOH and EM patients. By stratifying the M-MINI questionnaire results according to the number of psychiatric disorders, it was found that MOH patients had a more complex profile of psychiatric comorbidity. Furthermore, clinically relevant obsessive-compulsive disturbances for abused drugs assessed by Y-BOCS appeared to be more represented in the MOH group, whilst the prevalence of this trait in the EM group was comparable to that of HC (12.5%, 0.8% and 0%, respectively). CONCLUSIONS: Our study indicates the multiple presence of psychopathological comorbidities in patients with MOH. In light of this, it is recommended that the assessment of the psychopathological profile be included in an evaluation of MOH patients, allowing the clinician to more rapidly start an appropriate behavioural treatment, which would greatly improve MOH management.