Carlos Tobón

A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease

We previously reported age of onset (AOO) modifier genes in the worlds largest pedigree segregating early-onset Alzheimers disease (AD), caused by the p.Glu280Ala (E280A) mutation in the PSEN1 gene. Here we report the results of a targeted analysis of functional exonic variants in those AOO modifier genes in sixty individuals with PSEN1 E280A AD who were whole-exome genotyped for ~250,000 variants. Standard quality control, filtering, and annotation for functional variants were applied, and common functional variants located in those previously reported as AOO modifier loci were selected. Multiloci linear mixed-effects models were used to test the association between these variants and AOO. An exonic missense mutation in the G72 (DAOA) gene (rs2391191, P = 1.94 × 10−4, P FDR = 9.34 × 10−3) was found to modify AOO in PSEN1 E280A AD. Nominal associations of missense mutations in the CLUAP1 (rs9790, P = 7.63 × 10−3, P FDR = 0.1832) and EXOC2 (rs17136239, P = 0.0325, P FDR = 0.391) genes were also found. Previous studies have linked polymorphisms in the DAOA gene with the occurrence of neuropsychiatric symptoms such as depression, apathy, aggression, delusions, hallucinations, and psychosis in AD. Our findings strongly suggest that this new conspicuous functional AOO modifier within the G72 (DAOA) gene could be pivotal for understanding the genetic basis of AD.

Emotional processing in Colombian ex-combatants and its relationship with empathy and executive functions

In this work, the neural correlates of emotional processing in Colombian ex-combatants with different empathy profiles were compared to normal controls matched for age, gender and educational level. Forty ex-combatants and 20 non ex-combatants were recruited for this study. Empathy levels as well as executive functions were measured. Empathy level was used to create three groups. Group 1 (G1) included ex-combatants with normal empathy scores, and Group 2 included ex-combatants with low scores on at least one empathy sub-scales. In control group (Ctrl), participants with no antecedents of being combatants and with normal scores in empathy were included. Age, gender, educational and intelligence quotients level were controlled among groups. event-related potentials (ERPs) were recorded while individuals performed an affective picture processing task that included positive, neutral and negative emotional stimuli, which elicit an early modulation of emotion categorization (Early Posterior Negativity (EPN)) and late evaluative process (LPP). EPN differences were found among affective categories, but no group effects were observed at this component. LPP showed a main effect of category and group (higher amplitudes in ex-combatants). There was an inverse correlation between empathy and executive functions scores and ERPs. Results are discussed according to the impact of emotional processing on empathy profile.

Mutations modifying sporadic Alzheimer's disease age of onset

The identification of mutations modifying the age of onset (AOO) in Alzheimers disease (AD) is crucial for understanding the natural history of AD and, therefore, for early interventions. Patients with sporadic AD (sAD) from a genetic isolate in the extremes of the AOO distribution were whole‐exome genotyped. Single‐ and multi‐locus linear mixed‐effects models were used to identify functional variants modifying AOO. A posteriori enrichment and bioinformatic analyses were applied to evaluate the non‐random clustering of the associate variants to physiopathological pathways involved in AD. We identified more than 20 pathogenic, genome‐wide statistically significant mutations of major modifier effect on the AOO. These variants are harbored in genes implicated in neuron apoptosis, neurogenesis, inflammatory processes linked to AD, oligodendrocyte differentiation, and memory processes. This set of new genes harboring these mutations could be of importance for prediction, follow‐up and eventually as therapeutical targets of AD.

Dimensiones de la empatía en excombatientes del conflicto armado colombiano utilizando una escala estandarizada

INTRODUCTION Empathy is one of the main concepts of in social neurosciences. It is defined as a trait with multiple dimensions allowing individuals to place themselves in the emotional states of others. Colombia has an irregular, internal and long-lasting armed conflict which has been increasing its cruelty levels. OBJECTIVES to assess the empathy dimensions of 285 ex-combatants from the internal Colombian conflict, using the Interpersonal Reactivity Index(IRI) in Spanish. METHODOLOGY AND SUBJECTS: a sample of 285 male ex-combatants, 241 (84, 6%) males: 85,3% paramilitaries, and 14,7% guerillas. The 28 Item IRI questionnaires were administered. 3 exploratory factor analyses (EFA) were performed. Confirmatory factor analyses (CFA) were developed using structural equation procedures. RESULTS The first EFA obtained 9 factors (KMO=0,74, variance 54,7% and internal consistency (IC): 0,22 - 0,63). The second EFA produced 20 items with burdens above 0,4 and showed a 6-factor structure (KMO=0,70, variance 50,3%, IC: 0,37 - 0,63). The third EFA forced the 4 original IRI dimensions (KMO=0,74, variance 33,77, IC: 0,44 - 0,77. CFAs showed goodness of adjustment indexes adequate for the three models. The 4-factor model obtained the lowest value, while the 6-factor model obtained the highest. The 4- factor model showed the best IC. CONCLUSION The Spanish IRI administered to ex-combatants of the Colombian conflict has possible structures of 4, 6 and 9 factors. The best adjustment was for the 6-fctor. The 4-factor model exhibited the best IC.Resumen Introduccion La empatia es uno de los constructos de la llamadas neurociencias sociales. Se define como una disposicion de dimensiones multiples que permite colocarse en el estado emocional del otro. Colombia presenta un conflicto interno irregular prolongado, que ha venido deteriorandose en crueldad. Objetivos Evaluar las dimensiones de la empatia de 285 excombatientes del conflicto armado colombiano, usando el Indice de Reactividad Interpersonal (IRI) en espanol. Metodos y sujetos Se selecciono una muestra de 285 excombatientes, 241 (84,6%) hombres: 85,3% paramilitares y 14,7% guerrilleros. Se les aplico el IRI de 28 items. Se realizaron 3 analisis de factores exploratorios (AFE) y analisis factoriales confirmatorios (AFC), utilizando ecuaciones estructurales. Resultados Un primer AFE obtuvo 9 factores (KMO = 0,74 y 54,7% de varianza, consistencia interna [CI]: 0,22-0,63). Un segundo AFE con 20 items con cargas superiores a 0,4 mostro una estructura de 6 factores (KMO = 0,70, 50,3% de varianza; CI: 0,37-0,63). Un tercer AFE forzo las 4 dimensiones originales (KMO = 0,74, varianza 33,77% y CI: 0,44-0,77). El AFC mostro indices de bondad de ajuste adecuados para los 3 modelos. El de 4 factores obtuvo los mas bajos, y el de 6 factores, los mas altos. El modelo de 4 factores obtuvo la mejor CI. Conclusion El IRI en espanol en excombatientes del conflicto colombiano tiene estructuras posibles de 4, 6 y 9 factores. El mejor ajuste es la de 6 factores. La de 4 factores tuvo mejor CI.

The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer's disease, including a placebo-treated noncarrier cohort

Autosomal‐dominant Alzheimers disease (ADAD) represents a crucial population for identifying prevention strategies that might modify disease course for cognitively unimpaired individuals at high imminent risk for developing symptoms due to Alzheimers disease (AD), that is, who have “preclinical” AD. Crenezumab is an antiamyloid monoclonal antibody that binds monomeric and aggregated forms of amyloid β, with highest affinity for oligomers; it is in development for early stages of sporadic AD and for ADAD.

Perfil psiquiátrico, cognitivo y de reconocimiento de características emocionales de un grupo de excombatientes de los grupos armados ilegales en Colombia

INTRODUCTION Exposure to armed conflict produces biological adaptations oriented to handle the highly stressful conditions in war environments. The special features of The Colombian armed create a special scenario to evaluate the human behavior. OBJECTIVE In this study, psychiatric, cognitive and emotional processing characteristics of a group of Colombian armed illegal forces of ex-combatants are described. METHODS Sixty-three ex combatants and 22 controls were assessed with WAIS (IQ), INECO frontal screening (executive functions), Interpersonal Reactivity Index (empathy), emotional features recognition and MINI (psychiatric profile). RESULTS When compared to the control group, ex-combatants showed higher frequency of antisocial personality disorder (P=.031) and behavioral dissocial disorder (P=.017). In cognitive profile, the ex-combatants showed a lower score in the executive function test (Me=18.50; RQ=4.00), control (Me=23.00; RQ=5.25), with a poor personal distress in emphatic profile (Me=10.00; RQ=5.00) compared to control group (Me=37.00; RQ=7.25). CONCLUSIONS We found differences in cognitive and psychiatric profile in ex-combatants in comparison with controls.

Successful object encoding induces increased directed connectivity in presymptomatic early-onset Alzheimer's disease

Background: Recent studies report increases in neural activity in brain regions critical to episodic memory at preclinical stages of Alzheimer’s disease (AD). Although electroencephalography (EEG) is widely used in AD studies, given its non-invasiveness and low cost, there is a need to translate the findings in other neuroimaging methods to EEG. Objective: To examine how the previous findings using functional magnetic resonance imaging (fMRI) at preclinical stage in presenilin-1 E280A mutation carriers could be assessed and extended, using EEG and a connectivity approach. Methods: EEG signals were acquired during resting and encoding in 30 normal cognitive young subjects, from an autosomal dominant early-onset AD kindred from Antioquia, Colombia. Regions of the brain previously reported as hyperactive were used for connectivity analysis. Results: Mutation carriers exhibited increasing connectivity at analyzed regions. Among them, the right precuneus exhibited the highest changes in connectivity. Conclusion: Increased connectivity in hyperactive cerebral regions is seen in individuals, genetically-determined to develop AD, at preclinical stage. The use of a connectivity approach and a widely available neuroimaging technique opens the possibility to increase the use of EEG in early detection of preclinical AD.

Neurophysiological correlates in Mild Cognitive Impairment detected using group Independent Component Analysis.

Alzheimers disease is the most prevalent cause of dementia. Mild Cognitive Impairment (MCI) is defined as a grey area between intact cognitive functioning and clinical dementia. Electroencephalography (EEG) has been used to identify biomarkers in dementia. Currently, there is a great interest in translating the study from raw signals to signal generators, trying to keep the relationship with neurophysiology. In the current study, EEG recordings during an encoding task were acquired in MCI subjects and healthy controls. Data was decomposed using group Independent Component Analysis (gICA) and the most neuronal components were analyzed using Phase Intertrial Coherence (PIC) and Phase shift Intertrial Coherence (PsIC). MCI subjects exhibited an increase of PIC in the theta band, while controls showed increase in PsIC in the alpha band. Correlation between PIC and PsIC and clinical scales were also found. Those findings indicate that the methodology proposed based in gICA can help to extract information from EEG recordings with neurophysiological meaning.

The value of pre-screening in the alzheimer’s prevention initiative (api) autosomal dominant alzheimer’s disease trial

The Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) trial evaluates the anti-amyloid-β antibody crenezumab in cognitively unimpaired persons who, based on genetic background and age, are at high imminent risk of clinical progression, and provides a powerful test of the amyloid hypothesis. The Neurosciences Group of Antioquia implemented a pre-screening process with the goals of decreasing screen failures and identifying participants most likely to adhere to trial requirements of the API ADAD trial in cognitively unimpaired members of Presenilin1 E280A mutation kindreds. The pre-screening failure rate was 48.2%: the primary reason was expected inability to comply with the protocol, chiefly due to work requirements. More carriers compared to non-carriers, and more males compared to females, failed prescreening. Carriers with illiteracy or learning/comprehension difficulties failed pre-screening more than non-carriers. With the Colombian API Registry and our prescreening efforts, we randomized 169 30-60 year-old cognitively unimpaired carriers and 83 non-carriers who agreed to participate in the trial for at least 60 months. Our findings suggest multiple benefits of implementing a pre-screening process for enrolling prevention trials in ADAD.

Stop Saying That It Is Wrong! Psychophysiological, Cognitive, and Metacognitive Markers of Children’s Sensitivity to Punishment

Neurodevelopmental evidence suggests that children’s main decision-making strategy is to avoid options likely to induce punishment. However, the cognitive and affective factors contributing to children’s avoidance to high punishment frequency remain unknown. The present study explored psychophysiological, cognitive, and metacognitive processes associated with sensitivity to punishment frequency. We evaluated 54 participants (between 8 and 15 years old) with a modified Iowa Gambling Task for children (IGT-C) which included options with varying long-term profit and punishment frequencies. Skin conductance responses (SCRs) were recorded during this task. Additionally, we assessed IGT-C metacognitive knowledge, fluid intelligence, and executive functions. Participants exhibited behavioral avoidance and high anticipatory SCRs to options with high frequency of punishment. Moreover, age, IGT-C metacognitive knowledge, and inhibitory control were associated with individual differences in sensitivity to punishment frequency. Our results suggest that children’s preference for infrequently punished decisions is partially explained by psychophysiological signals as well as task complexity and development of cognitive control.