Publications by authors named "Ramon Novell"

12 Publications

  • Page 1 of 1

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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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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January 2020

The Girona declaration on borderline intellectual functioning.

Lancet Psychiatry 2020 03;7(3):e8

Centre for Mental Health Research, Research School of Population Health, ANU College of Health and Medicine, Australian National University.

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March 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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December 2019

A phase 1, randomized double-blind, placebo controlled trial to evaluate safety and efficacy of epigallocatechin-3-gallate and cognitive training in adults with Fragile X syndrome.

Clin Nutr 2020 02 25;39(2):378-387. Epub 2019 Mar 25.

IMIM-Hospital del Mar Medical Research Institute, E-08003 Barcelona, Spain; University Pompeu Fabra (CEXS-UPF), E-08003 Barcelona, Spain; Center for Genomic Regulation (CRG), E-08003 Barcelona, Spain; CIBER of Rare Diseases (CIBERER), E-08003 Barcelona, Spain; The Barcelona Institute of Science and Technology, E-08003 Barcelona, Spain. Electronic address:

Background & Aims: Despite the wide spectrum of experimental compounds tested in clinical trials, there is still no proven pharmacological treatment available for Fragile-X syndrome (FXS), since several targeted clinical trials with high expectations of success have failed to demonstrate significant improvements. Here we tested epigallocatechin-3-gallate (EGCG) as a treatment option for ameliorating core cognitive and behavioral features in FXS.

Methods: We conducted preclinical studies in Fmr1 knockout mice (Fmr1-/y) using novel object-recognition memory paradigm upon acute EGCG (10 mg/kg) administration. Furthermore we conducted a double-blind placebo-controlled phase I clinical trial (TESXF; NCT01855971). Twenty-seven subjects with FXS (18-55 years) were administered of EGCG (5-7 mg/kg/day) combined with cognitive training (CT) during 3 months with 3 months of follow-up after treatment discontinuation.

Results: Preclinical studies showed an improvement in memory using the Novel Object Recognition paradigm. We found that FXS patients receiving EGCG + CT significantly improved cognition (visual episodic memory) and functional competence (ABAS II-Home Living skills) in everyday life compared to subjects receiving Placebo + CT.

Conclusions: Phase 2 clinical trials in larger groups of subjects are necessary to establish the therapeutic potential of EGCG for the improvement of cognition and daily life competences in FXS.
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February 2020

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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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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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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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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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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January 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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September 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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November 2014