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INTRODUCTION This study investigates primary lateral sclerosis (PLS) as a rare manifestation of the presenilin 1 (PSEN1) NM_000021 c.851C > T p.Pro284Leu variant in three siblings of a Colombian family, outlining its clinical and neuropathological features and their relationship to Alzheimer's disease (AD). METHODS Data were gathered using clinical evaluations, next‐generation genetic sequencing, magnetic resonance imaging, biomarker analysis, and neuropathological examination. RESULTS Carriers of the PSEN1 Pro284Leu variant exhibited classic PLS symptoms, including unilateral onset and bulbar syndromes, along with cognitive decline. Neuropathology showed corticospinal tract degeneration without amyloid beta deposition in spinal white matter. DISCUSSION Our findings suggest an overlap between PLS and AD pathology in PSEN1 variant carriers. Results support considering PLS when diagnosing AD‐related motor syndromes and including PSEN1 evaluation when performing genetic testing for PLS. The study highlights the need for further research to clarify the PLS–AD relationship, informing future treatments and clinical trials. Highlights Pathogenic variants in presenilin 1 (PSEN1) can manifest as hereditary primary lateral sclerosis PSEN1 Pro284Leu carriers present motor, cognitive, and behavioral alterations  Cases had corticospinal tract microgliosis and severe Aβ pathology in motor cortex  There was no evidence of amyloid deposition in the spinal cord white matter  All the neuropathology images are available for online visualization  Myelin pallor in the spinal cord is confined to the lateral corticospinal tracts

INTRODUCTION This study involved evaluating a tailored genetic counseling and testing (GCT) protocol for families at risk of autosomal dominant Alzheimer's disease (ADAD) in Latin America (LatAm), focusing on essential cultural and regional adaptations. METHODS We conducted a non‐randomized controlled trial among ADAD families in Colombia and Argentina. Participants were categorized based on their decision to learn their genetic status (GS), with further comparisons between mutation‐positive versus mutation‐negative participants who learned their status. Psychological impacts were measured using validated scales for anxiety and depression. RESULTS Of the 122 eligible participants, 97 completed the GCT protocol, and 87 opted to learn their GS. There were no clinically significant differences in psychological distress between those who learned their status and those who did not, nor between mutation‐positive and mutation‐negative individuals. DISCUSSION The GCT protocol effectively managed psychological impacts in ADAD families and was positively received, demonstrating the importance of culturally adapted GCT protocols. Highlights We examined the adaptation and efficacy of a GCT protocol in LatAm for families at risk of ADAD. The GCT protocol mitigated psychological distress among at‐risk ADAD families. The study confirms the protocol's cultural appropriateness and psychological safety. Future studies should explore the long‐term psychological and public health impacts of GCT and use of GCT for treatment options.

Thirteen PSEN1 genetic variants associated with Autosomal Dominant Alzheimer's Disease (ADAD) have been identified in Colombia, providing valuable insights into the preclinical stages of the disease. This study characterizes the clinical and neuropsychological phenotypes of carriers and non-carriers from families with nine pathogenic PSEN1 variants: Glu280Ala, Gln223Lys, His163Arg, Ile162Ser, Ile416Thr, Leu173Phe, Pro264Leu, Pro284Leu, and Thr119Ile. We analyzed baseline clinical and neuropsychological characteristics of participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study (DIAN-OBS), including individuals at both preclinical and symptomatic stages. Descriptive statistics were used to summarize sociodemographic, clinical, and cognitive features, depending on data distribution, and we used Kruskal-Wallis to explore differences between groups. Group comparisons were based on PSEN1 variant and clinical diagnosis, and the age at onset (AAO) of the affected parent was used to determine each subject's estimated years to symptom onset (EYO). The sample included 61 participants (55.7% female), aged 18-58, with a median education of 12 years (IQR: 10-14). Of these, 77% were cognitively unimpaired (MMSE: 30, IQR: 29-30; CDR-SB: 0), 15% had mild cognitive impairment (MMSE: 25.1, SD: 3.6; CDR-SB: 1.9, SD: 1.1), and 8% had dementia (MMSE: 21, SD: 6.5; CDR-SB: 3.9, SD: 3.1). All symptomatic individuals exhibited primarily amnestic symptoms, and one carrier of the PSEN1-Pro284Leu variant presented motor signs. As expected-given that most participants were in preclinical stages-no statistically significant differences in clinical or cognitive features were observed across variants. Twenty-eight participants were in the primary prevention range (EYO: -11 to -35 years) and thirty-three in the secondary prevention range (EYO: -10 to +13 years). Parental age at onset differed by variant location: intramembranous (50 years, IQR: 46-53), cytoplasmic (40.5 years, SD: 4.6), and extracellular (45 years, IQR: 45-48). These findings are consistent with existing literature and underscore the value of characterizing preclinical ADAD cohorts, supported by biomarkers, to guide early diagnostic and therapeutic strategies, especially in the context of clinical trials. We expect to have complete fluid and neuroimaging biomarker and follow-up data for the presentation of these results.

Background Thirteen PSEN1 genetic variants associated with Autosomal Dominant Alzheimer’s Disease (ADAD) have been identified in Colombia, providing valuable insights into the preclinical stages of the disease. This study characterizes the clinical and neuropsychological phenotypes of carriers and non‐carriers from families with nine pathogenic PSEN1 variants: Glu280Ala, Gln223Lys, His163Arg, Ile162Ser, Ile416Thr, Leu173Phe, Pro264Leu, Pro284Leu, and Thr119Ile. Method We analyzed baseline clinical and neuropsychological characteristics of participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study (DIAN‐OBS), including individuals at both preclinical and symptomatic stages. Descriptive statistics were used to summarize sociodemographic, clinical, and cognitive features, depending on data distribution, and we used Kruskal‐Wallis to explore differences between groups. Group comparisons were based on PSEN1 variant and clinical diagnosis, and the age at onset (AAO) of the affected parent was used to determine each subject's estimated years to symptom onset (EYO). Results The sample included 61 participants (55.7% female), aged 18–58, with a median education of 12 years (IQR: 10–14). Of these, 77% were cognitively unimpaired (MMSE: 30, IQR: 29–30; CDR‐SB: 0), 15% had mild cognitive impairment (MMSE: 25.1, SD: 3.6; CDR‐SB: 1.9, SD: 1.1), and 8% had dementia (MMSE: 21, SD: 6.5; CDR‐SB: 3.9, SD: 3.1). All symptomatic individuals exhibited primarily amnestic symptoms, and one carrier of the PSEN1‐Pro284Leu variant presented motor signs. As expected—given that most participants were in preclinical stages—no statistically significant differences in clinical or cognitive features were observed across variants. Twenty‐eight participants were in the primary prevention range (EYO: ‐11 to ‐35 years) and thirty‐three in the secondary prevention range (EYO: ‐10 to +13 years). Parental age at onset differed by variant location: intramembranous (50 years, IQR: 46–53), cytoplasmic (40.5 years, SD: 4.6), and extracellular (45 years, IQR: 45–48). Conclusion These findings are consistent with existing literature and underscore the value of characterizing preclinical ADAD cohorts, supported by biomarkers, to guide early diagnostic and therapeutic strategies, especially in the context of clinical trials. We expect to have complete fluid and neuroimaging biomarker and follow‐up data for the presentation of these results.

Background This study evaluates a tailored genetic counseling and testing (GTC) protocol for families at risk of Autosomal Dominant Alzheimer ´s Disease (ADAD) in Latin America, focusing on the essential cultural and regional adaptations. Several factors may influence the decision of whether family members decide to learn genetic status. Although the main drivers influencing the decisions to seek genetic testing have been widely studied in High‐Income Counties (HIC), these questions remain relatively unknown in Low and Middle‐Income countries (LMICs) such as those in Latin America (LatAm). Method The primary aim of this study was to investigate the psychosocial impact of genetic testing in asymptomatic individuals from families with ADAD. We conducted a non randomized, controlled trial among ADAD families in Colombia and Argentina. The primary outcome included change from baseline in depression and general anxiety in the test group relative to the control group. Participants were categorized based on their decision to learn their genetic status, with further comparisons between mutation‐positive versus mutation‐negative individuals within those informed. Psychological impacts were measuring using validated scales for depression and anxiety in the group relative to the control group. Result Of the 122 eligible participants, 97 completed the GTC protocol; 87 opted to learn their genetic status. There were no clinically significant differences in psychological distress between those who learned their status and those who did not, nor between mutation‐positive and mutation‐negative individuals. Mutation‐positive carriers who learned their genetic status experienced a statistically significant increase in depression scores but remained below the cut‐off point considered indicative of clinically significant depression. Conclusion Our primary finding is showed no clinically meaningful differences in distress‐related outcomes between individuals learning their genetic status relative to those who didn’t. Our findings confirm that genetic testing is well‐tolerated when using a protocol that provides screening, education, counseling, and follow‐up sessions. In addition, we provide preliminary insights into the psychological impact associated with learning one's genetic status in familial AD, contributing significantly to the field of medical genetics in the region.

This study evaluates a tailored genetic counseling and testing (GTC) protocol for families at risk of Autosomal Dominant Alzheimer ´s Disease (ADAD) in Latin America, focusing on the essential cultural and regional adaptations. Several factors may influence the decision of whether family members decide to learn genetic status. Although the main drivers influencing the decisions to seek genetic testing have been widely studied in High-Income Counties (HIC), these questions remain relatively unknown in Low and Middle-Income countries (LMICs) such as those in Latin America (LatAm). The primary aim of this study was to investigate the psychosocial impact of genetic testing in asymptomatic individuals from families with ADAD. We conducted a non randomized, controlled trial among ADAD families in Colombia and Argentina. The primary outcome included change from baseline in depression and general anxiety in the test group relative to the control group. Participants were categorized based on their decision to learn their genetic status, with further comparisons between mutation-positive versus mutation-negative individuals within those informed. Psychological impacts were measuring using validated scales for depression and anxiety in the group relative to the control group. Of the 122 eligible participants, 97 completed the GTC protocol; 87 opted to learn their genetic status. There were no clinically significant differences in psychological distress between those who learned their status and those who did not, nor between mutation-positive and mutation-negative individuals. Mutation-positive carriers who learned their genetic status experienced a statistically significant increase in depression scores but remained below the cut-off point considered indicative of clinically significant depression. Our primary finding is showed no clinically meaningful differences in distress-related outcomes between individuals learning their genetic status relative to those who didn't. Our findings confirm that genetic testing is well-tolerated when using a protocol that provides screening, education, counseling, and follow-up sessions. In addition, we provide preliminary insights into the psychological impact associated with learning one's genetic status in familial AD, contributing significantly to the field of medical genetics in the region.

Overweight and obesity are now considered a worldwide pandemic and a growing public health problem with severe economic and social consequences. Adipose tissue is an organ with neuroimmune-endocrine functions, which participates in homeostasis. So, adipocyte hypertrophy and hyperplasia induce a state of chronic inflammation that causes changes in the brain and induce neuroinflammation. Studies with obese animal models and obese patients have shown a relationship between diet and cognitive decline, especially working memory and learning deficiencies. Here we analyze how obesity-related peripheral inflammation can affect central nervous system physiology, generating neuroinflammation. Given that the blood-brain barrier is an interface between the periphery and the central nervous system, its altered physiology in obesity may mediate the consequences on various cognitive processes. Finally, several interventions, and the use of natural compounds and exercise to prevent the adverse effects of obesity in the brain are also discussed.

Abnormal development of the ocular anterior segment may lead to a spectrum of clinical phenotypes ranging from primary congenital glaucoma (PCG) to variable anterior segment dysgenesis (ASD). The main objective of this study was to identify the genetic alterations underlying recessive congenital glaucoma with ASD (CG-ASD). Next-generation DNA sequencing identified rare biallelic CPAMD8 variants in four patients with CG-ASD and in one case with PCG. CPAMD8 is a gene of unknown function and recently associated with ASD. Bioinformatic and in vitro functional evaluation of the variants using quantitative reverse transcription PCR and minigene analysis supported a loss-of-function pathogenic mechanism. Optical and electron microscopy of the trabeculectomy specimen from one of the CG-ASD cases revealed an abnormal anterior chamber angle, with altered extracellular matrix, and apoptotic trabecular meshwork cells. The CPAMD8 protein was immunodetected in adult human ocular fluids and anterior segment tissues involved in glaucoma and ASD (i.e., aqueous humor, non-pigmented ciliary epithelium, and iris muscles), as well as in periocular mesenchyme-like cells of zebrafish embryos. CRISPR/Cas9 disruption of this gene in F0 zebrafish embryos (96 hpf) resulted in varying degrees of gross developmental abnormalities, including microphthalmia, pharyngeal maldevelopment, and pericardial and periocular edemas. Optical and electron microscopy examination of these embryos showed iridocorneal angle hypoplasia (characterized by altered iris stroma cells, reduced anterior chamber, and collagen disorganized corneal stroma extracellular matrix), recapitulating some patients’ features. Our data support the notion that CPAMD8 loss-of-function underlies a spectrum of recessive CG-ASD phenotypes associated with extracellular matrix disorganization and provide new insights into the normal and disease roles of this gene.

Obesity is a heterogeneous condition comprising a continuum of phenotypes with various metabolic and inflammatory profiles. Metabolically healthy obesity (MHO) identifies individuals with obesity but a relatively preserved metabolic state, although little is known about the gut microbiome features underlying this phenotype. Here, we analyzed gut microbial network structures of 931 individuals living with metabolically healthy non-obesity (MHNO), MHO, metabolically unhealthy non-obesity (MUNO), and metabolically unhealthy obesity (MUO), performing cross-sectional analyses on feces shotgun metagenomics data. Individuals with MHNO and MHO harbor more robust and functionally cohesive microbial networks, while communities from MUO and MUNO phenotypes exhibit a potentially dysbiotic state with reduced connectivity. A nutritional intervention cohort showed an improvement in network connectivity in parallel with metabolic improvements. Our findings show differences in microbial connectivity and association patterns across metabolic and obesity phenotypes, shedding light on how distinct microbial network structures may associate with host metabolic health and disease. Here, the authors show that microbiome network topology associates with metabolic health across obesity phenotypes, with reduced connectivity in metabolically unhealthy states and improved network structure following a nutritional intervention.

Celiac disease (CD) is a chronic immune-mediated systemic disorder caused by consuming gluten in genetically susceptible individuals. There is currently no cure for CD, and the most effective treatment is maintaining a strict, lifelong gluten-free diet (GFD). This nutritional therapy aims to prevent the immune reaction triggered by gluten and promote the healing of the intestinal lining, resolving the clinical, serological, and histological abnormalities within 6–12 months. However, up to 30% of patients may continue to experience symptoms or exhibit laboratory abnormalities or intestinal inflammation suggestive of active CD, despite following a GFD. This challenge, which encompasses various diagnoses, is known as nonresponsive celiac disease (NRCD). In this study, we explored the role of intestinal microbiota in causing NRCD, finding an association between the persistence of symptoms and changes in mucosal integrity biomarkers, with different gut microbiome structures among NRCD patients, indicating a significant role of the microbiome in NRCD.