Brain Volumetric Analysis Using Artificial Intelligence Software in Premanifest Huntington's Disease Individuals from a Colombian Caribbean Population.

Background and objectives: The premanifest phase of Huntington's disease (HD) is characterized by the absence of motor symptoms and exhibits structural changes in imaging that precede clinical manifestation. This study aimed to analyze volumetric changes identified through brain magnetic resonance imaging (MRI) processed using artificial intelligence (AI) software in premanifest HD individuals, focusing on the relationship between CAG triplet expansion and structural biomarkers. Methods: The study included 36 individuals descending from families affected by HD in the Department of Atlántico. Sociodemographic data were collected, followed by peripheral blood sampling to extract genomic DNA for quantifying CAG trinucleotide repeats in the Huntingtin gene. Brain volumes were evaluated using AI software (Entelai/IMEXHS, v4.3.4) based on MRI volumetric images. Correlations between brain volumes and variables such as age, sex, and disease status were determined. All analyses were conducted using SPSS (v. IBM SPSS Statistics 26), with significance set at p < 0.05. Results: The analysis of brain volumes according to CAG repeat expansion shows that individuals with ≥40 repeats evidence significant increases in cerebrospinal fluid (CSF) volume and subcortical structures such as the amygdalae and left caudate nucleus, along with marked reductions in cerebral white matter, the cerebellum, brainstem, and left pallidum. In contrast, those with <40 repeats show minimal or moderate volumetric changes, primarily in white matter and CSF. Conclusions: These findings suggest that CAG expansion selectively impacts key brain regions, potentially influencing the progression of Huntington's disease, and that AI in neuroimaging could identify structural biomarkers long before clinical symptoms appear.

Theory of Mind in Huntington's Disease: A Systematic Review of 20 Years of Research.

Background: People with Huntington's disease (HD) exhibit neurocognitive alterations throughout the disease, including deficits in social cognitive processes such as Theory of Mind (ToM). Objective: The aim is to identify methodologies and ToM instruments employed in HD, alongside relevant findings, within the scientific literature of the past two decades. Methods: We conducted a comprehensive search for relevant papers in the SCOPUS, PubMed, APA-PsyArticles, Web of Science, Redalyc, and SciELO databases. In the selection process, we specifically focused on studies that included individuals with a confirmed genetic status of HD and investigated ToM functioning in patients with and without motor symptoms. The systematic review followed the PRISMA protocol. Results: A total of 27 papers were selected for this systematic review, covering the period from 2003 to 2023. The findings consistently indicate that ToM is globally affected in patients with manifest motor symptoms. In individuals without motor symptoms, impairments are focused on the affective dimensions of ToM. Conclusions: Based on our analysis, affective ToM could be considered a potential biomarker for HD. Therefore, it is recommended that ToM assessment be included as part of neuropsychological evaluation protocols in clinical settings. Suchinclusion could aid in the identification of early stages of the disease and provide new opportunities for treatment, particularly with emerging drugs like antisense oligomers. The Prospero registration number for this review is CRD42020209769.

Uncovering the Genetic and Molecular Features of Huntington's Disease in Northern Colombia.

Huntington's disease (HD) is a genetic disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene. Juan de Acosta, Atlántico, a city located on the Caribbean coast of Colombia, is home to the world's second-largest HD pedigree. Here, we include 291 descendants of this pedigree with at least one family member with HD. Blood samples were collected, and genomic DNA was extracted. We quantified the HTT CAG expansion using an amplicon sequencing protocol. The genetic heterogeneity was measured as the ratio of the mosaicism allele's read peak and the slippage ratio of the allele's read peak from our sequence data. The statistical and bioinformatic analyses were performed with a significance threshold of p < 0.05. We found that the average HTT CAG repeat length in all participants was 21.91 (SD = 8.92). Of the 291 participants, 33 (11.3%, 18 females) had a positive molecular diagnosis for HD. Most affected individuals were adults, and the most common primary and secondary alleles were 17/7 (CAG/CCG) and 17/10 (CAG/CCG), respectively. The mosaicism increased with age in the participants with HD, while the slippage analyses revealed differences by the HD allele type only for the secondary allele. The slippage tended to increase with the HTT CAG repeat length in the participants with HD, but the increase was not statistically significant. This study analyzed the genetic and molecular features of 291 participants, including 33 with HD. We found that the mosaicism increased with age in the participants with HD, particularly for the secondary allele. The most common haplotype was 17/7_17/10. The slippage for the secondary allele varied by the HD allele type, but there was no significant difference in the slippage by sex. Our findings offer valuable insights into HD and could have implications for future research and clinical management.

Machine Learning Prediction of ADHD Severity: Association and Linkage to ADGRL3, DRD4, and SNAP25.

OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNPs) in the ADGRL3, DRD4, and SNAP25 genes are associated with and predict ADHD severity in families from a Caribbean community. METHOD: ADHD severity was derived using latent class cluster analysis of DSM-IV symptomatology. Family-based association tests were conducted to detect associations between SNPs and ADHD severity latent phenotypes. Machine learning algorithms were used to build predictive models of ADHD severity based on demographic and genetic data. RESULTS: Individuals with ADHD exhibited two seemingly independent latent class severity configurations. SNPs harbored in DRD4, SNAP25, and ADGRL3 showed evidence of linkage and association to symptoms severity and a potential pleiotropic effect on distinct domains of ADHD severity. Predictive models discriminate severe from non-severe ADHD in specific symptom domains. CONCLUSION: This study supports the role of DRD4, SNAP25, and ADGRL3 genes in outlining ADHD severity, and a new prediction framework with potential clinical use.

Impulsive and Omission Errors: Potential Temporal Processing Endophenotypes in ADHD.

Temporal processing (TP) is associated with functions such as perception, verbal skills, temporal perspective, and future planning, and is intercorrelated with working memory, attention, and inhibitory control, which are highly impaired in individuals with attention deficit hyperactivity disorder (ADHD). Here we evaluate TP measures as potential endophenotypes in Caribbean families ascertained from probands affected by ADHD. A total of 232 individuals were recruited and clinically evaluated using an extensive battery of neuropsychological tasks and reaction time (RT)-based task paradigms. Further, the heritability (genetic variance underpinning phenotype) was estimated as a measure of the genetics apportionment. A predictive framework for ADHD diagnosis was derived using these tasks. We found that individuals with ADHD differed from controls in neuropsychological tasks assessing mental control, visual-verbal memory, verbal fluency, verbal, and semantic fluency. In addition, TP measures such as RT, errors, and variability were also affected in individuals with ADHD. Moreover, we determined that only omission and commission errors had significant heritability. In conclusion, we have disentangled omission and commission errors as possible TP endophenotypes in ADHD, which can be suitable to assess the neurobiological and genetic basis of ADHD. A predictive model using these endophenotypes led to remarkable sensitivity, specificity, precision and classification rate for ADHD diagnosis, and may be a useful tool for patients' diagnosis, follow-up, and longitudinal assessment in the clinical setting.

ADGRL3, FGF1 and DRD4: Linkage and Association with Working Memory and Perceptual Organization Candidate Endophenotypes in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurobehavioral disorder that affects children worldwide, with detrimental long-term consequences in affected individuals. ADHD-affected patients display visual-motor and visuospatial abilities and skills that depart from those exhibited by non-affected individuals and struggle with perceptual organization, which might partially explain impulsive responses. Endophenotypes (quantifiable or dimensional constructs that are closely related to the root cause of the disease) might provide a more powerful and objective framework for dissecting the underlying neurobiology of ADHD than that of categories offered by the syndromic classification. In here, we explore the potential presence of the linkage and association of single-nucleotide polymorphisms (SNPs), harbored in genes implicated in the etiology of ADHD (ADGRL3, DRD4, and FGF1), with cognitive endophenotypes related to working memory and perceptual organization in 113 nuclear families. These families were ascertained from a geographical area of the Caribbean coast, in the north of Colombia, where the community is characterized by its ethnic diversity and differential gene pool. We found a significant association and linkage of markers ADGRL3-rs1565902, DRD4-rs916457 and FGF1-rs2282794 to neuropsychological tasks outlining working memory and perceptual organization such as performance in the digits forward and backward, arithmetic, similarities, the completion of figures and the assembly of objects. Our results provide strong support to understand ADHD as a combination of working memory and perceptual organization deficits and highlight the importance of the genetic background shaping the neurobiology, clinical complexity, and physiopathology of ADHD. Further, this study supplements new information regarding an ethnically diverse community with a vast African American contribution, where ADHD studies are scarce.

Genetic Variation Underpinning ADHD Risk in a Caribbean Community.

Attention Deficit Hyperactivity Disorder (ADHD) is a highly heritable and prevalent neurodevelopmental disorder that frequently persists into adulthood. Strong evidence from genetic studies indicates that single nucleotide polymorphisms (SNPs) harboured in the ADGRL3 (LPHN3), SNAP25, FGF1, DRD4, and SLC6A2 genes are associated with ADHD. We genotyped 26 SNPs harboured in genes previously reported to be associated with ADHD and evaluated their potential association in 386 individuals belonging to 113 nuclear families from a Caribbean community in Barranquilla, Colombia, using family-based association tests. SNPs rs362990-SNAP25 (T allele; p = 2.46 × 10-4), rs2282794-FGF1 (A allele; p = 1.33 × 10-2), rs2122642-ADGRL3 (C allele, p = 3.5 × 10-2), and ADGRL3 haplotype CCC (markers rs1565902-rs10001410-rs2122642, OR = 1.74, Ppermuted = 0.021) were significantly associated with ADHD. Our results confirm the susceptibility to ADHD conferred by SNAP25, FGF1, and ADGRL3 variants in a community with a significant African American component, and provide evidence supporting the existence of specific patterns of genetic stratification underpinning the susceptibility to ADHD. Knowledge of population genetics is crucial to define risk and predict susceptibility to disease.

ADGRL3 (LPHN3) variants predict substance use disorder.

Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within ADGRL3 are associated with SUD, a disorder that is frequently co-morbid with ADHD. Using family-based, case-control, and longitudinal samples from disparate regions of the world (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 genetic information to predict SUD susceptibility. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying ADGRL3 as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD.

Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer's Disease.

The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer's disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. We recruited 78 individuals with AD from the Paisa genetic isolate in Antioquia, Colombia. These individuals belong to the world largest multigenerational and extended pedigree segregating AD as a consequence of a dominant fully penetrant mutation in the PSEN1 gene and exhibit an AOO ranging from the early 1930s to the late 1970s. To shed light on the genetic underpinning that could explain the large spread of the age of onset (AOO) of AD, 64 single nucleotide polymorphisms (SNP) associated with neuroanatomical, cardiovascular, and cognitive measures in AD were genotyped. Standard quality control and filtering procedures were applied, and single- and multi-locus linear mixed-effects models were used to identify AOO-associated SNPs. A full two-locus interaction model was fitted to define how identified SNPs interact to modulate AOO. We identified two key epistatic interactions between the APOE*E2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~ 8 years (95% CI 3.2-12.7, P = 1.83 × 10-3) and ~ 7.6 years (95% CI 3.3-11.8, P = 8.69 × 10-4), respectively, and validated our previous finding indicating that APOE*E2 delays AOO of AD in PSEN1 E280 mutation carriers. This new evidence involving APOE*E2 as an AOO delayer could be used for developing precision medicine approaches and predictive genomics models to potentially determine AOO in individuals genetically predisposed to AD.

Prepotent response inhibition and reaction times in children with attention deficit/hyperactivity disorder from a Caribbean community.

Impairment in inhibitory control has been postulated as an underlying hallmark of attention deficit/hyperactivity disorder (ADHD), which can be utilized as a quantitative trait for genetic studies. Here, we evaluate whether inhibitory control, measured by simple automatized prepotent response (PR) inhibition variables, is a robust discriminant function for the diagnosis of ADHD in children and can be used as an endophenotype for future genetic studies. One hundred fifty-two school children (30.9% female, 67.8% with ADHD) were recruited. The ADHD checklist was used as the screening tool, whilst the DSM-IV Mini International Neuropsychiatry Interview, neurologic interview and neurologic examination, and the WISC III FSIQ test were administered as the gold standard procedure to assert ADHD diagnosis. A Go/No-Go task using a naturalistic and automatized visual signal was administered. A linear multifactor model (MANOVA) was fitted to compare groups including ADHD status, age, and gender as multiple independent factors. Linear discriminant analysis and the receiver operating characteristic curve were used to assess the predictive performance of PR inhibition variables for ADHD diagnosis. We found that four variables of prepotent response reaction time- and prepotent response inhibition established statistically significant differences between children with and without ADHD. Furthermore, these variables generated a strong discriminant function with a total classification capability of 73, 84% specificity, 68% sensitivity, and 90% positive predictive value for ADHD diagnosis, which support reaction times as a candidate endophenotype that could potentially be used in future ADHD genetic research.

Déficit en habilidades sociales en niños con Trastorno por Déficit de Atención-Hiperactividad, evaluados con la Escala BASC / Déficit em habilidades sociais em crianças com Transtorno por Déficit de Atenção-Hiperatividade, avaliados com a escala BASC / Social skills deficits in children diagnosed with Attention Deficit Hyperactivity Disorder evaluated with the BASC scale

Se analizaron las Habilidades Sociales (HS) de 159 niños de ambos sexos, escolarizados, con Trastorno por Déficit de Atención-Hiperactividad (TDAH), entre los 6 y los 11 años de edad. La valoración de las HS se realizó con la escala Behavioral Assessment System for Children para padres y maestros. Los resultados mostraron que los niños con TDAH presentan puntajes más bajos en las dimensiones de habilidades sociales como escuchar, esperar turnos, reconocer señales sociales y tener capacidad de adaptabilidad. Sin embargo, en compañerismo, los participantes con TDAH combinado poseen habilidades semejantes a los no afectados. Esto replantea lo encontrado en la mayoría de los estudios en donde únicamente se evidencian deficiencias...

The study analyzed the Social Skills (SS) of 159 male and female school children between the ages of 6 and 11, suffering from Attention Deficit Hyperactivity Disorder (ADHD). The evaluation of SS was carried out with the Behavioral Assessment System for Children for use by parents and teachers. The results showed that children with ADHD feature lower scores in social skills such as listening, respecting turns, recognizing social signals, and adaptability. However, participants with ADHD proved to have companionship skills similar to those of unaffected children. This makes it necessary to rethink the findings of the majority of studies, which only reveal deficiencies...

Analisaram-se as Habilidades Sociais (HS) de 159 crianças, escolarizadas, com Transtorno por Déficit de Atenção-Hiperatividade (TDAH), entre 6 e 11 anos de idade. A valoração das HS se realizou com a escala Behavioral Assessment System for Children para pais e mestres. Os resultados mostraram que as crianças com TDAH apresentam pontuações mais baixas nas dimensões de HS como escutar, esperar a vez, reconhecer sinais sociais e ter capacidade de adaptabilidade. Contudo, em companheirismo, os participantes com TDAH combinado possuem habilidades semelhantes aos não afetados. Isso repropõe o encontrado na maioria dos estudos nos quais unicamente se evidenciam deficiências...

Fenotipo comportamental evaluado con una escala multidimensional de la conducta en niños y adolescentes de 30 familias con trastorno de atención-hiperactividad / Conduct phenotype detected with the behavioral assessment system for children in 30 ADHD families

INTRODUCCIÓN: el sistema de evaluación de la conducta para niños (sigla del inglés: BASC) es una escala para medir la conducta y la personalidad de los niños y adolescentes.OBJETIVO: establecer el fenotipo cuantitativo del comportamiento en 30 familias nucleares de Barranquilla con un caso índice de un niño afectado con TDAH, utilizando la escala BASC. MATERIAL Y MÉTODOS: se seleccionaron 50 niños y adolescentes de ambos generos, pertenecientes a 30 familias con un caso índice de TDAH. Para el diagnóstico, se aplicó una entrevista psiquiátrica estructurada, evaluación médica y neuropsicológica. Los padres y maestros llenaron el BASC acerca de los niños y adolescentes.RESULTADOS: de acuerdo con las respuestas de los padres, el fenotipo estaría formado por síntomas de inatención en la escala clínica, con diferencias muy significativas entre los grupos y un tamaño del efecto enorme (1,45); además, informan la presencia significativamente más frecuente de síntomas atípicos en el grupo de TDAH, con un tamaño del efecto grande (0,7). En la escala de adaptación, los no afectados tienen habilidades sociales significativamente mejores, con un tamaño del efecto muy grande (1,23). En la escala clínica de maestros, los síntomas de hiperactividad muestran puntuaciones significativamente mayores en el grupo de afectados, con un tamaño del efecto muy grande (1,13); los síntomas de inatención también producen diferencias estadísticamente significativas con tamaño del efecto grande (0,98). El fenotipo cuantitativo más detectado por maestros es el de los problemas académicos, con un tamaño del efecto enorme (1,4).CONCLUSIONES: la escala multidimensional BASC permitió detectar posibles fenotipos cuantitativos del comportamiento en las familias estudiadas.