Publications by authors named "Susanna Esteba-Castillo"

17 Publications

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Hypersynchronized MEG brain networks in patients with mild cognitive impairment and Alzheimer's disease in Down syndrome.

Brain Connect 2021 Apr 15. Epub 2021 Apr 15.

Universidad Politecnica de Madrid, 16771, Centro de Tecnología Biomédica, Madrid, Madrid, Spain.

Introduction: The majority of individuals with Down syndrome (DS) show signs of Alzheimer's disease (AD) neuropathology in their fourth decade. However, there is a lack of specific markers for characterizing the disease stages while considering this population's differential features.

Methods: Forty-one DS individuals participated in the study and were classified into three groups according to their clinical status: Alzheimer's disease (AD-DS), mild cognitive impairment (MCI-DS), and controls (CN-DS). We performed an exhaustive neuropsychological evaluation and assessed brain Functional Connectivity (FC) from magnetoencephalographic recordings.

Results: Compared to CN-DS, both MCI-DS and AD-DS showed a pattern of increased FC within the high alpha band. The neuropsychological assessment showed a generalized cognitive impairment, primarily affecting mnestic functions, in MCI-DS and, more pronouncedly, in AD-DS.

Discussion: These findings might help to characterize the AD-continuum in DS and in the population with typical development. Additionally, they support the role of the excitatory/inhibitory imbalance as a key pathophysiological factor in AD.
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http://dx.doi.org/10.1089/brain.2020.0897DOI Listing
April 2021

Altered Gesture Imitation and Brain Anatomy in Adult Prader-Willi Syndrome Patients.

J Int Neuropsychol Soc 2021 Mar 4:1-13. Epub 2021 Mar 4.

Specialized Service in Mental Health and Intellectual Disability Department, Institut Assistència Sanitària (IAS), Parc Hospitalari Martí i Julià, Girona, Spain.

Objective: To explore motor praxis in adults with Prader-Willi syndrome (PWS) in comparison with a control group of people with intellectual disability (ID) and to examine the relationship with brain structural measurements.

Method: Thirty adult participants with PWS and 132 with ID of nongenetic etiology (matched by age, sex, and ID level) were assessed using a comprehensive evaluation of the praxis function, which included pantomime of tool use, imitation of meaningful and meaningless gestures, motor sequencing, and constructional praxis.

Results: Results support specific praxis difficulties in PWS, with worse performance in the imitation of motor actions and better performance in constructional praxis than ID peers. Compared with both control groups, PWS showed increased gray matter volume in sensorimotor and subcortical regions. However, we found no obvious association between these alterations and praxis performance. Instead, praxis scores correlated with regional volume measures in distributed apparently normal brain areas.

Conclusions: Our findings are consistent in showing significant impairment in gesture imitation abilities in PWS and, otherwise, further indicate that the visuospatial praxis domain is relatively preserved. Praxis disability in PWS was not associated with a specific, focal alteration of brain anatomy. Altered imitation gestures could, therefore, be a consequence of widespread brain dysfunction. However, the specific contribution of key brain structures (e.g., areas containing mirror neurons) should be more finely tested in future research.
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http://dx.doi.org/10.1017/S1355617721000060DOI Listing
March 2021

Efficacy and safety of a GABAergic drug (Gamalate® B6): effects on behavior and cognition in young adults with borderline-to-mild intellectual developmental disabilities and ADHD.

Drugs Context 2020 23;9:212601. Epub 2020 Jan 23.

Specialized Service in Mental Health and Intellectual Disability (SEMSDI), Parc Hospitalàri Martí i Julià, Instituto de Asistencia Sanitaria, Girona, Spain.

Background: We evaluated Gamalate® B6 (GB6) in patients with borderline intellectual functioning (BIF) or mild intellectual development disability (IDD).

Patients And Methods: This was a prospective phase IV observational pilot study in 30 patients who underwent neuropsychological evaluation during treatment with GB6 for 12 weeks.

Results: In comparison with baseline, the responses were positive, with a significant improvement in hyperactivity (51.7%), irritability (35.5%), and logorrhea (50%), and no sedative effect. The Clinical Global Impressions - Severity (CGI-S) score was much improved or very much improved in 73% of cases. Reaction time was better with fewer errors, thus indicating an improvement in attentional processes. A statistically significant result was obtained for the number of movements used to solve the problem and for the total number of correctly solved problems.

Conclusion: In this pilot study, GB6 was effective and well tolerated in cases of ADHD and challenging behavior in young adults with borderline-to-mild BIF/IDD. However, given the small number of patients involved and the uncontrolled nature of the study, these results should be viewed cautiously.
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http://dx.doi.org/10.7573/dic.212601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048157PMC
January 2020

Neuropsychological and neurophysiological characterization of mild cognitive impairment and Alzheimer's disease in Down syndrome.

Neurobiol Aging 2019 12 3;84:70-79. Epub 2019 Aug 3.

Center for Biomedical Technology, Laboratory of Cognitive and Computational Neuroscience, Technical University of Madrid, Campus Montegancedo, Madrid, Spain; Department of Legal Medicine, Psychiatry and Pathology, Complutense University of Madrid, Spain, Madrid, Spain.

Down syndrome (DS) has been considered a unique model for the investigation of Alzheimer's disease (AD) but intermediate stages in the continuum are poorly defined. Considering this, we investigated the neurophysiological (i.e., magnetoencephalography [MEG]) and neuropsychological patterns of mild cognitive impairment (MCI) and AD in middle-aged adults with DS. The sample was composed of four groups: Control-DS (n = 14, mean age 44.64 ± 3.30 years), MCI-DS (n = 14, 51.64 ± 3.95 years), AD-DS (n = 13, 53.54 ± 6.58 years), and Control-no-DS (healthy controls, n = 14, 45.21 ± 4.39 years). DS individuals were studied with neuropsychological tests and MEG, whereas the Control-no-DS group completed only the MEG session. Our results showed that the AD-DS group exhibited a significantly poorer performance as compared with the Control-DS group in all tests. Furthermore, this effect was crucially evident in AD-DS individuals when compared with the MCI-DS group in verbal and working memory abilities. In the neurophysiological domain, the Control-DS group showed a widespread increase of theta activity when compared with the Control-no-DS group. With disease progression, this increased theta was substituted by an augmented delta, accompanied with a reduction of alpha activity. Such spectral pattern-specifically observed in occipital, posterior temporal, cuneus, and precuneus regions-correlated with the performance in cognitive tests. This is the first MEG study in the field incorporating both neuropsychological and neurophysiological information, and demonstrating that this combination of markers is sensitive enough to characterize different stages along the AD continuum in DS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.07.017DOI Listing
December 2019

Compulsions in Prader-Willi syndrome: occurrence and severity as a function of genetic subtype.

Actas Esp Psiquiatr 2019 May 1;47(3):79-87. Epub 2019 May 1.

Specialized Service in Mental Health and Intellectual Disability (SESM-DI), and Girona Biomedical Research Institute (IdibGi), Parc Hospitalari Martí i Julià, Institut d´Assistència Sanitària, Salt (Girona), Spain Department of Psychology, Philipps-Universität Marburg, Marburg, Germany.

Introduction: Compulsions are among the most typical behaviors in Prader-Willi syndrome (PWS). The most frequent causes of PWS are deletion of the genes located in the segment 15q11-q13 of the paternal allele and maternal uniparental disomy of cromosome 15. The aim of the present work was to study compulsive behavior in a sample of adults with PWS and analyze potential differences as a function of the genetic cause/subtype.

Material And Methods: In the 27 study participants, existence of type I deletion (n=7), type II deletion (n=13), and maternal disomy (n=7) was determined by means of genetic tests. The Yale-Brown Obsessive Compulsive Scale, the Compulsive Behavior Checklist, and the Repetitive Behavior Questionnaire were used to assess occurrence and severity of compulsions.

Results: Most of the participants showed compulsive behavior, the most frequent compulsions were those of inappropriate grooming (skin picking) and order (hoarding). The occurrence of compulsions was less frequent in the maternal disomy group than in the deletion groups. Severe compulsions were more frequent in those participants with type II deletion than in the other groups.

Conclusions: Differences in occurrence and severity of compulsions exist as a function of PWS genetic subtype. Our results support the idea that individuals with maternal disomy are less affected by compulsive behavior. More research on the severity of compulsions as a function of deletion type should be done, as the studies conducted so far have shown contradictory results.
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May 2019

Lack of response to disgusting food in the hypothalamus and related structures in Prader Willi syndrome.

Neuroimage Clin 2019 4;21:101662. Epub 2019 Jan 4.

Endocrinology and Nutrition Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT- UAB, 08208 Sabadell, Spain.

Objective: To investigate, based on a putative abnormal neural processing of disgusting signals in Prader Willi syndrome (PWS) patients, the brain response to visual representations of disgusting food in PWS using functional MRI (fMRI).

Methods: Twenty-one genetically-confirmed PWS patients, 30 age- and sex-matched and 28 BMI-matched control subjects viewed a movie depicting disgusting food-related scenes interspersed with scenes of appetizing food while fMRI was acquired. Brain activation maps were compared between groups and correlated with disgust and hunger ratings.

Results: At the cortical level, the response to disgusting food representations in PWS patients was qualitatively similar to that of control subjects, albeit less extensive, and engaged brain regions typically related to visually-evoked disgust, such as the anterior insula/frontal operculum, the lateral frontal cortex and visual areas. By contrast, activation was almost absent in limbic structures directly concerned with the regulation of instinctive behavior robustly activated in control subjects, such as the hypothalamus, amygdala/hippocampus and periaqueductal gray.

Conclusions: Our study provides novel insights into the neural substrates of appetite control in a genetically-mediated cause of obesity. The presence of significant cortical changes further indicates that PWS patients consciously process disgusting stimuli, but the virtual absence of response in deep, limbic structures suggests that disgusting signals do not adequately reach the primary brain system for the appetite control.
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http://dx.doi.org/10.1016/j.nicl.2019.101662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412080PMC
January 2020

High Incidence of Copy Number Variants in Adults with Intellectual Disability and Co-morbid Psychiatric Disorders.

Behav Genet 2018 07 7;48(4):323-336. Epub 2018 Jun 7.

Genetics lab, UDIAT-centre diagnostic. Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí I3PT. Universitat Autònoma de Barcelona, C/Parc Tauli,1, 08208, Sabadell, Barcelona, Spain.

A genetic analysis of unexplained mild-moderate intellectual disability and co-morbid psychiatric or behavioural disorders is not systematically conducted in adults. A cohort of 100 adult patients affected by both phenotypes were analysed in order to identify the presence of copy number variants (CNVs) responsible for their condition identifying a yield of 12.8% of pathogenic CNVs (19% when including clinically recognizable microdeletion syndromes). Moreover, there is a detailed clinical description of an additional 11% of the patients harbouring possible pathogenic CNVs-including a 7q31 deletion (IMMP2L) in two unrelated patients and duplications in 3q29, 9p24.2p24.1 and 15q14q15.1-providing new evidence of its contribution to the phenotype. This study adds further proof of including chromosomal microarray analysis (CMA) as a mandatory test to improve the diagnosis in the adult patients in psychiatric services.
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http://dx.doi.org/10.1007/s10519-018-9902-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028865PMC
July 2018

A longitudinal study of brain anatomy changes preceding dementia in Down syndrome.

Neuroimage Clin 2018 28;18:160-166. Epub 2018 Jan 28.

Specialized Service in Mental Health and Intellectual Disability, Institut Assistència Sanitària (IAS), Parc Hospitalari Martí i Julià, 17190 Girona, Spain.

Background: We longitudinally assessed Down syndrome individuals at the age of risk of developing dementia to measure changes in brain anatomy and their relationship to cognitive impairment progression.

Methods: Forty-two Down syndrome individuals were initially included, of whom 27 (mean age 46.8 years) were evaluable on the basis of completing the 2-year follow-up and success in obtaining good quality MRI exams. Voxel-based morphometry was used to estimate regional brain volumes at baseline and follow-up on 3D anatomical images. Longitudinal volume changes for the group and their relationship with change in general cognitive status and specific cognitive domains were mapped.

Results: As a group, significant volume reduction was identified in the substantia innominata region of the basal forebrain, hippocampus, lateral temporal cortex and left arcuate fasciculus. Volume reduction in the substantia innominata and hippocampus was more prominent in individuals whose clinical status changed from cognitively stable to mild cognitive impairment or dementia during the follow-up. Relevantly, longitudinal memory score change was specifically associated with volume change in the hippocampus, prospective memory with prefrontal lobe and verbal comprehension with language-related brain areas.

Conclusions: Results are notably concordant with the well-established anatomical changes signaling the progression to dementia in Alzheimer's disease, despite the dense baseline pathology that developmentally accumulates in Down syndrome. This commonality supports the potential value of Down syndrome as a genetic model of Alzheimer's neurodegeneration and may serve to further support the view that Down syndrome patients are best candidates to benefit from treatment research in Alzheimer's disease.
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http://dx.doi.org/10.1016/j.nicl.2018.01.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984600PMC
January 2019

Neurodevelopmental risk copy number variants in adults with intellectual disabilities and comorbid psychiatric disorders.

Br J Psychiatry 2018 05;212(5):287-294

Department of Human Genetics,Centre for Human Genetics,University Hospitals Leuven,Leuven,Belgium.

Background: Copy number variants (CNVs) are established risk factors for neurodevelopmental disorders. To date the study of CNVs in psychiatric illness has focused on single disorder populations. The role of CNVs in individuals with intellectual disabilities and psychiatric comorbidities are less well characterised.AimsTo determine the type and frequency of CNVs in adults with intellectual disabilities and comorbid psychiatric disorders.

Method: A chromosomal microarray analysis of 599 adults recruited from intellectual disabilities psychiatry services at three European sites.

Results: The yield of pathogenic CNVs was high - 13%. Focusing on established neurodevelopmental disorder risk loci we find a significantly higher frequency in individuals with intellectual disabilities and comorbid psychiatric disorder (10%) compared with healthy controls (1.2%, P<0.0001), schizophrenia (3.1%, P<0.0001) and intellectual disability/autism spectrum disorder (6.5%, P < 0.00084) populations.

Conclusions: In the largest sample of adults with intellectual disabilities and comorbid psychiatric disorders to date, we find a high rate of pathogenic CNVs. This has clinical implications for the use of genetic investigations in intellectual disability psychiatry.Declaration of interestNone.
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http://dx.doi.org/10.1192/bjp.2017.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083594PMC
May 2018

Mapping the sequence of brain events in response to disgusting food.

Hum Brain Mapp 2018 01 11;39(1):369-380. Epub 2017 Oct 11.

Endocrinology and Nutrition Department, Sabadell University Hospital (UAB), Corporació Sanitària Parc Taulí, Sabadell, 08208, Spain.

Warning signals indicating that a food is potentially dangerous may evoke a response that is not limited to the feeling of disgust. We investigated the sequence of brain events in response to visual representations of disgusting food using a dynamic image analysis. Functional MRI was acquired in 30 healthy subjects while they were watching a movie showing disgusting food scenes interspersed with the scenes of appetizing food. Imaging analysis included the identification of the global brain response and the generation of frame-by-frame activation maps at the temporal resolution of 2 s. Robust activations were identified in brain structures conventionally associated with the experience of disgust, but our analysis also captured a variety of other brain elements showing distinct temporal evolutions. The earliest events included transient changes in the orbitofrontal cortex and visual areas, followed by a more durable engagement of the periaqueductal gray, a pivotal element in the mediation of responses to threat. A subsequent core phase was characterized by the activation of subcortical and cortical structures directly concerned not only with the emotional dimension of disgust (e.g., amygdala-hippocampus, insula), but also with the regulation of food intake (e.g., hypothalamus). In a later phase, neural excitement extended to broad cortical areas, the thalamus and cerebellum, and finally to the default mode network that signaled the progressive termination of the evoked response. The response to disgusting food representations is not limited to the emotional domain of disgust, and may sequentially involve a variety of broadly distributed brain networks. Hum Brain Mapp 39:369-380, 2018. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866415PMC
January 2018

Validation and Normalization of the Tower of London-Drexel University Test 2nd Edition in an Adult Population with Intellectual Disability.

Span J Psychol 2017 Jul 20;20:E32. Epub 2017 Jul 20.

Parc Hospitalari Martí i Julià(Spain).

Despite how important it is to assess executive functioning in persons with Intellectual Disability (ID), instruments adapted and validated for this population are scarce. This study's primary goal was to find evidence for the validity of the ID version of the Tower of London (TOLDXtm) test in persons with mild (IDMi) and moderate (IDMo) levels of ID with Down Syndrome (DS). A multicenter study was carried out. Subjects (n = 63, ≥ 39 years old) had DS with mild (n = 39) or moderate ID (n = 24) with no minor neurocognitive disorder or Alzheimer's disease. Assessment protocol: TOLDXtm for ID, Kaufman Brief Intelligence Test Second Edition (K-BIT II), Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and Others with Intellectual Disabilities (CAMDEX-DS), Weigl's Color-Form Sorting Test (WCFST), Barcelona Test for Intellectual Disability (BT-ID), and the Behavior Rating Inventory of Executive Function (BRIEF-P). The internal consistency (IDMi and IDMo), factor structure of the different subscales, and relationship between TOLDXtm subscales and other cognitive measures (BT-ID, WCFST, and BRIEF-P) were analyzed. A normative data table with ID population quartiles is provided. TOLDXtm for ID showed a robust one factor structure and coherentassociations with other, related neuropsychological instruments. Significant differences between IDMi and IDMo on movement-related variables like Correct (Corr; p = .002) and Moves (Mov; p = .042) were observed, along with good internal consistency values, Corr (α = .75), Mov (α = .52). Regarding internal consistency, no between-groups differences were observed (all p-value > 0.05). The TOLDXtm for ID is thus an instrument, supported by good validity evidence, to evaluate problem-solving and planning in ID. It distinguishes between individuals with mild and moderate ID, and is highly associated with other measures of executive functioning.
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http://dx.doi.org/10.1017/sjp.2017.30DOI Listing
July 2017

Anomalous White Matter Structure and the Effect of Age in Down Syndrome Patients.

J Alzheimers Dis 2017 ;57(1):61-70

Integrative Pharmacology and Neuroscience Systems Research Group, Hospital del Mar Medical Research Institute, Barcelona, Spain.

Background: Neural tissue alterations in Down syndrome are fully expressed at relatively late developmental stages. In addition, there is an early presence of neurodegenerative changes in the late life stages.

Objective: The aims of this study were both to characterize white matter abnormalities in the brain of adult Down syndrome patients using diffusion tensor imaging (DTI) and to investigate whether degenerative alterations in white matter structure are detectable before dementia is clinically evident.

Methods: Forty-five adult non-demented Down syndrome patients showing a wide age range (18-52 years) and a matched 45-subject control group were assessed. DTI fractional anisotropy (FA) brain maps were generated and selected cognitive tests were administered.

Results: Compared with healthy controls, non-demented Down syndrome patients showed lower DTI FA in white matter involving the major pathways, but with more severe alterations in the frontal-subcortical circuits. White matter FA decreased with age at a similar rate in both DS and control groups.

Conclusions: Our results contribute to characterizing the expression of white matter structural alterations in adult Down syndrome. However, an accelerated aging effect was not demonstrated, which may suggest that the FA measurements used are not sufficiently sensitive or, alternatively, age-related white matter neurodegeneration is not obvious prior to overt clinical dementia.
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http://dx.doi.org/10.3233/JAD-161112DOI Listing
February 2018

Translation and validation of the Spanish version of the Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD).

Rev Psiquiatr Salud Ment 2018 Jul - Sep;11(3):141-150. Epub 2016 Dec 21.

Servicio Especializado en Salud Mental y Discapacidad Intelectual (SESM-DI), Parc Hospitalari Martí i Julià, Institut d'Assistència Sanitària, Salt, Girona, España.

Introduction: The Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD) is a brief instrument that assesses functioning in people with intellectual development disorder and mental health problems/behaviour disorders. The aim of the present study was to examine the evidence on the validity of the scores based on the Spanish version of the HoNOS-LD.

Material And Methods: The study included 111 participants that were assessed by the Spanish version of the HoNOS-LD and other questionnaires that measured different variables related to the scale. Thirty-three participants were assessed by 2 examiners, and retested 7 days later, in order to study inter-examiner reliability and test-retest reliabilities.

Results: Based on clinical and conceptual criteria, and on the results of the parallel analysis, a factorial solution with one factor was selected. Internal consistency was good (Omega coefficient of 0.87). Inter-examiner and test-retest reliabilities were excellent (intraclass correlation coefficients of 0.95 and 0.98, respectively). Correlations between sections of the HoNOS-LD and the related instruments showed the expected direction, and were highly significant (P<.001), and the HoNOS-LD score increased with the intensity of the support required by the participants. These results showed evidence of the validity of association with other external variables.

Conclusions: The Spanish version of the HoNOS-LD is a brief, valid and reliable instrument, which will enable a routine assessment of functioning for different uses, including diagnosis and intervention.
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http://dx.doi.org/10.1016/j.rpsm.2016.11.002DOI Listing
December 2018

Lack of Postprandial Peak in Brain-Derived Neurotrophic Factor in Adults with Prader-Willi Syndrome.

PLoS One 2016;11(9):e0163468. Epub 2016 Sep 29.

Department of Endocrinology and Nutrition, Sabadell University Hospital, Corporació Sanitària Parc Taulí, Sabadell, Spain, Autonomous University of Barcelona, Bellaterra, Spain.

Context: Prader-Willi syndrome (PWS) is characterized by severe hyperphagia. Brain-derived neurotrophic factor (BDNF) and leptin are reciprocally involved in energy homeostasis.

Objectives: To analyze the role of BDNF and leptin in satiety in genetic subtypes of PWS.

Design: Experimental study.

Setting: University hospital.

Subjects: 90 adults: 30 PWS patients; 30 age-sex-BMI-matched obese controls; and 30 age-sex-matched lean controls.

Interventions: Subjects ingested a liquid meal after fasting ≥10 hours.

Main Outcome Measures: Leptin and BDNF levels in plasma extracted before ingestion and 30', 60', and 120' after ingestion. Hunger, measured on a 100-point visual analogue scale before ingestion and 60' and 120' after ingestion.

Results: Fasting BDNF levels were lower in PWS than in controls (p = 0.05). Postprandially, PWS patients showed only a truncated early peak in BDNF, and their BDNF levels at 60' and 120' were lower compared with lean controls (p<0.05). Leptin was higher in PWS patients than in controls at all time points (p<0.001). PWS patients were hungrier than controls before and after eating. The probability of being hungry was associated with baseline BDNF levels: every 50-unit increment in BDNF decreased the odds of being hungry by 22% (OR: 0.78, 95%CI: 0.65-0.94). In uniparental disomy, the odds of being hungry decreased by 66% (OR: 0.34, 90%CI: 0.13-0.9). Postprandial leptin patterns did no differ among genetic subtypes.

Conclusions: Low baseline BDNF levels and lack of postprandial peak may contribute to persistent hunger after meals. Uniparental disomy is the genetic subtype of PWS least affected by these factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163468PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042477PMC
September 2016

Anomalous basal ganglia connectivity and obsessive-compulsive behaviour in patients with Prader Willi syndrome.

J Psychiatry Neurosci 2016 06;41(4):261-71

From the MRI Research Unit, CRC Mar, Hospital del Mar, Barcelona, Spain (Pujol, Blanco-Hinojo, Deus, Macià); the Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21, Barcelona, Spain (Pujol); the Human Pharmacology and Clinical Neurosciences, Hospital del Mar Medical Research Institute, Barcelona, Spain (Blanco-Hinojo); the Parc Hospitalari Martí i Julià, Salt, Girona, Spain (Esteba-Castillo, Novell-Alsina); the Endocrinology and Nutrition Department. Sabadell University Hospital (UAB), Corporació Sanitària Parc Taulí, Sabadell, Spain (Caixàs, Rigla); the Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Melbourne, Australia (Harrison); the Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Lleida, Spain (Bueno); the Department of Clinical and Health Psychology, Autonomous University of Barcelona, Spain (Deus); and the Rheumatology Department, Hospital del Mar, Barcelona, Spain (Onaindia).

Background: Prader Willi syndrome is a genetic disorder with a behavioural expression characterized by the presence of obsessive-compulsive phenomena ranging from elaborate obsessive eating behaviour to repetitive skin picking. Obsessive-compulsive disorder (OCD) has been recently associated with abnormal functional coupling between the frontal cortex and basal ganglia. We have tested the potential association of functional connectivity anomalies in basal ganglia circuits with obsessive-compulsive behaviour in patients with Prader Willi syndrome.

Methods: We analyzed resting-state functional MRI in adult patients and healthy controls. Whole-brain functional connectivity maps were generated for the dorsal and ventral aspects of the caudate nucleus and putamen. A selected obsessive-compulsive behaviour assessment included typical OCD compulsions, self picking and obsessive eating behaviour.

Results: We included 24 adults with Prader Willi syndrome and 29 controls in our study. Patients with Prader Willi syndrome showed abnormal functional connectivity between the prefrontal cortex and basal ganglia and within subcortical structures that correlated with the presence and severity of obsessive-compulsive behaviours. In addition, abnormally heightened functional connectivity was identified in the primary sensorimotor cortex-putamen loop, which was strongly associated with self picking. Finally, obsessive eating behaviour correlated with abnormal functional connectivity both within the basal ganglia loops and between the striatum and the hypothalamus and the amygdala.

Limitations: Limitations of the study include the difficulty in evaluating the nature of content of obsessions in patients with Prader Willi Syndrome and the risk of excessive head motion artifact on brain imaging.

Conclusion: Patients with Prader Willi syndrome showed broad functional connectivity anomalies combining prefrontal loop alterations characteristic of OCD with 1) enhanced coupling in the primary sensorimotor loop that correlated with the most impulsive aspects of the behaviour and 2) reduced coupling of the ventral striatum with limbic structures for basic internal homeostasis that correlated with the obsession to eat.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915935PMC
http://dx.doi.org/10.1503/jpn.140338DOI Listing
June 2016

A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.

Mol Genet Genomic Med 2014 Nov 18;2(6):512-21. Epub 2014 Aug 18.

Laboratori de Genètica, UDIAT-Centre Diagnòstic, Corporació Sanitària Parc Taulí, Institut Universitari Parc Tauli-UAB Sabadell, Spain.

Deletions in the 2p16.3 region that includes the neurexin (NRXN1) gene are associated with intellectual disability and various psychiatric disorders, in particular, autism and schizophrenia. We present three unrelated patients, two adults and one child, in whom we identified an intragenic 2p16.3 deletion within the NRXN1 gene using an oligonucleotide comparative genomic hybridization array. The three patients presented dual diagnosis that consisted of mild intellectual disability and autism and bipolar disorder. Also, they all shared a dysmorphic phenotype characterized by a long face, deep set eyes, and prominent premaxilla. Genetic analysis of family members showed two inherited deletions. A comprehensive neuropsychological examination of the 2p16.3 deletion carriers revealed the same phenotype, characterized by anxiety disorder, borderline intelligence, and dysexecutive syndrome. The cognitive pattern of dysexecutive syndrome with poor working memory and reduced attention switching, mental flexibility, and verbal fluency was the same than those of the adult probands. We suggest that in addition to intellectual disability and psychiatric disease, NRXN1 deletion is a risk factor for a characteristic cognitive and dysmorphic profile. The new cognitive phenotype found in the 2p16.3 deletion carriers suggests that 2p16.3 deletions might have a wide variable expressivity instead of incomplete penetrance.
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http://dx.doi.org/10.1002/mgg3.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303221PMC
November 2014

[Adaptation and validation of CAMDEX-DS (Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and others with intellectual disabilities) in Spanish population with intellectual disabilities].

Rev Neurol 2013 Oct;57(8):337-46

Parc Hospitalari Marti i Julia, 17190 Salt, Espana.

Introduction: Dementia caused by Alzheimer's disease commonly affects the adult population with Down's syndrome. This population presents two characteristic clinical features: a semiologic pattern that differs from the typical Alzheimer's disease, and previous intellectual deficits that may confound the clinical diagnosis. There is a clear need to validate specific instruments adapted to Spanish population.

Aim: To adapt and to validate CAMDEX-DS (Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and Others with Intellectual Disabilities) in Spanish population.

Patients And Methods: 146 patients with intellectual disability (mild to moderate) were recruited and assessed with CAMDEX-DS, K-BIT I and DMR tests. Test-retest reliability, inter-rater concordance and validity statistic were performed between CAMDEX-DS and clinical diagnosis. This is an observational, multicenter, cross-sectional and validation study.

Results: Test-retest and inter-rater reliability achieved kappa coefficient values of 0.92 and 0.91, respectively. Agreement (kappa index) for CAMDEX-DS on clinical diagnosis compared to other clinical criteria was high: CAMDEX-DS vs DSM-IV (kappa = 0.95; p < 0,001); CAMDEX-DS vs ICD-10 (kappa = 0.97; p < 0.001). All item-test correlations ranged between 0,31 and 0,69. Internal reliability-calculated using Chronbach's alpha scored 0.93.

Conclusions: The Spanish version of CAMDEX-DS is a valid instrument with high applicability for people with intellectual disability. It shows good psychometric properties. The Cambridge Cognitive Examination for Older Adults with Down's Syndrome (CAMCOG-DS) can set two key points by the level of intellectual disability on the suspicion of cognitive impairment in people with Down's syndrome.
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October 2013