Andone Sistiaga

Neurocognitive disorder detection based on feature vectors extracted from VBM analysis of structural MRI

Dementia is a growing concern due to the aging process of the western societies. Non-invasive detection is therefore a high priority research endeavor. In this paper we report results of classification systems applied to the feature vectors obtained by a feature extraction method computed on structural magnetic resonance imaging (sMRI) volumes for the detection of two neurological disorders with cognitive impairment: myotonic dystrophy of type 1 (MD1) and Alzheimer disease (AD). The feature extraction process is based on the voxel clusters detected by voxel-based morphometry (VBM) analysis of sMRI upon a set of patient and control subjects. This feature extraction process is specific for each kind of disease and is grounded on the findings obtained by medical experts. The 10-fold cross-validation results of several statistical and neural network based classification algorithms trained and tested on these features show high specificity and moderate sensitivity of the classifiers, suggesting that the approach is better suited for rejecting than for detecting early stages of the diseases.

Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing

Tau is the proteinaceous component of intraneuronal aggregates common to neurodegenerative diseases called Tauopathies, including myotonic dystrophy type 1. In myotonic dystrophy type 1, the presence of microtubule-associated protein Tau aggregates is associated with a mis-splicing of Tau. A toxic gain-of-function at the ribonucleic acid level is a major etiological factor responsible for the mis-splicing of several transcripts in myotonic dystrophy type 1. These are probably the consequence of a loss of muscleblind-like 1 (MBNL1) function or gain of CUGBP1 and ETR3-like factor 1 (CELF1) splicing function. Whether these two dysfunctions occur together or separately and whether all mis-splicing events in myotonic dystrophy type 1 brain result from one or both of these dysfunctions remains unknown. Here, we analyzed the splicing of Tau exons 2 and 10 in the brain of myotonic dystrophy type 1 patients. Two myotonic dystrophy type 1 patients showed a mis-splicing of exon 10 whereas exon 2-inclusion was reduced in all myotonic dystrophy type 1 patients. In order to determine the potential factors responsible for exon 10 mis-splicing, we studied the effect of the splicing factors muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1), CUGBP1 and ETR3-like factor 2 (CELF2), and CUGBP1 and ETR3-like factor 4 (CELF4) or a dominant-negative CUGBP1 and ETR-3 like factor (CELF) factor on Tau exon 10 splicing by ectopic expression or siRNA. Interestingly, the inclusion of Tau exon 10 is reduced by CUGBP1 and ETR3-like factor 2 (CELF2) whereas it is insensitive to the loss-of-function of muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1) gain-of-function, or a dominant-negative of CUGBP1 and ETR-3 like factor (CELF) factor. Moreover, we observed an increased expression of CUGBP1 and ETR3-like factor 2 (CELF2) only in the brain of myotonic dystrophy type 1 patients with a mis-splicing of exon 10. Taken together, our results indicate the occurrence of a mis-splicing event in myotonic dystrophy type 1 that is induced neither by a loss of muscleblind-like 1 (MBNL1) function nor by a gain of CUGBP1 and ETR3-like factor 1 (CELF1) function but is rather associated to CUGBP1 and ETR3-like factor 2 (CELF2) gain-of-function.

Genes related to iron metabolism and susceptibility to Alzheimer's disease in Basque population.

Alzheimers disease (AD) is the most common dementing disorder and presents with a progressive and irreversible cognitive decline of gradual onset. To date, several reports have involved iron in AD physiopathology. In this study, we have analysed TFC2 variant and HFE mutations (H63D and C282Y) in 211 AD patients and 167 controls recruited from an area of the Basque Country. Furthermore, we have studied APOE genotype as it is a well-known risk factor for AD. APOE epsilon 4 allele was associated with an increased risk of AD and an earlier age at onset, whereas no association was found between TFC2 or HFE C282Y mutation and disease susceptibility. The frequency of H63D mutation was higher in control population (29.9%) than in AD patients (18%), suggesting a protective role of this allele on AD either due to the presence of the mutation itself or through the effect of other related genes in the ancestral haplotype in which it is included.

Distinctive age-related temporal cortical thinning in asymptomatic granulin gene mutation carriers

Studies in asymptomatic granulin gene (GRN) mutation carriers are essential to improve our understanding of the pattern and timing of early morphologic brain changes in frontotemporal lobar degeneration. The main objectives of this study were to assess the effect of age in cortical thickness changes (CTh) in preclinical GRN mutation carriers and to study the relationship of CTh with cognitive performance in GRN mutation carriers. We calculated CTh maps in 13 asymptomatic carriers of the c.709-1G>A GRN mutation and 13 age- and sex-matched healthy subjects. Asymptomatic GRN mutation carriers presented different patterns of age-related cortical thinning in the right superior temporal and middle temporal gyri and the banks of the superior temporal sulcus bilaterally when compared with controls. Cortical thickness was correlated with neuropsychological test scores: Trail Making Tests A and B, and the Boston Naming Test. Distinctive age-related cortical thinning in asymptomatic GRN mutation carriers in lateral temporal cortices suggests an early and disease-specific effect in these areas.

Cognitive function in facioscapulohumeral dystrophy correlates with the molecular defect

Previous studies based on case descriptions and neuroradiological findings have suggested central nervous system (CNS) involvement in facioscapulohumeral dystrophy. The aim of this work is to explore the relationship between cognitive/personality pattern and the underlying molecular defect for this muscular dystrophy. We performed a wide‐ranging neuropsychological assessment of 34 molecularly confirmed facioscapulohumeral dystrophy patients and 49 control subjects, all of whom also received the Millon‐II Multiaxial Clinical Inventory (MCMI‐II). Patients and controls show mild learning‐level differences in the neuropsychological profile, and only the hysteriform scale is statistically higher in patients than controls. The patients’ intelligence quotient (IQ) is related to the size of the deleted fragment but not to the degree of muscular impairment. The results of this study indicate a cut‐off point and two distinct cognitive profiles in facioscapulohumeral dystrophy, depending on the patients’ molecular defect: patients with a fragment size >24 kb show a relatively normal cognitive pattern, whereas those with a fragment size ≤24 kb show a significantly reduced IQ and difficulties with verbal function and visuo‐constructive tasks. This work provides more evidence for the involvement of the CNS in facioscapulohumeral dystrophy and suggests that the fragment size should be taken into account in the clinical management of facioscapulohumeral dystrophy as it has a predictive value on the cognitive phenotype.

Social cognition in myotonic dystrophy type 1: Specific or secondary impairment?

Aims The cognitive profile of Myotonic Dystrophy type 1 (DM1) has been described in recent decades. Moreover, DM1 patients show lowered social engagement and difficulties in social-cognitive functions. The aim of the present study is to explore whether social cognition impairment is present in DM1 taking into account the overall cognitive condition. Method 38 patients and a control group paired in age and gender participated in the study. All the participants had an IQ within the normal range. Subjects were administered an abbreviated neuropsychological battery which comprised a facial emotion recognition test (POFA) and Faux Pas Test, as well as a self-report questionnaire on cognitive and affective empathy (TECA). Results Statistically significant differences were found only for facial emotion recognition (U = 464.0, p = .006) with a moderate effect size (.31), with the controls obtaining a higher score than the patients. Analyzing each emotion separately, DM1 patients scored significantly lower than controls on the recognition of anger and disgust items. Emotion recognition did not correlate with genetic load, but did correlate negatively with age. No differences were found between patients and controls in any of the other variables related to Theory of Mind (ToM) and empathy. Conclusion DM1 does not manifest specific impairments in ToM since difficulties in this area predominantly rely on the cognitive demand of the tasks employed. However, a more basic process such as emotion recognition appears as a core deficit. The role of this deficit as a marker of aging related decline is discussed.

Mis-splicing of Tau Exon 2 and Exon 10 in myotonic dystrophy brain would result from different mechanisms

MYOTONIC DYSTROPHYBRAINWOULDRESULT FROM DIFFERENT MECHANISMS Marie-Laure Caillet-Boudin, Claire-Marie Dhaenens, MarieLise Frandemiche, Helene Tran, Celine Carpentier, FranciscoJose Fernandez-Gomez, Andone Sistiaga, Maria Goicoechea, EdwigeVan Brussel, Helene Obriot, Sabiha Eddarkaoui, Marie-Helene Gavaert, Bernard Sablonniere, Adolfo Lopez-de-munain, Luc Buee, Susanna Schraen, Nicolas Sergeant, Inserm-Univ. Lille, Lille, France; Inserm, U837-1, Univ. Lille Nord de France, IMPRT, Centre Jean-Pierre Aubert, Lille, France, Lille, France; Neurological Department and Experimental Unit, Donostia Hospital, San Sebastian, Spain, San Sebastian, Spain; 4 Neuropathological Department, Regional University Hospital Centre, Lille, France., Lille, France; Neurological Department and Experimental Unit, Donostia Hospital, San Sebastian, Spain, Lille, France.