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Frontotemporal dementia (FTD) remains one of the most common forms of early-onset dementia (45 to 65 years). FTD consists clinically and pathologically of a heterogeneous group of disorders characterized by progressive frontal and temporal lobe atrophy. Thirty to fifty percent of cases have a family history of the disease. In this work we aimed to characterize pathogenic variants implicated in familial FTD cases in a cohort from Argentina. A total of 43 patients (23 women, 20 men) meeting clinical criteria for probable behavioral variant-FTD, semantic or nonfluent primary progressive aphasia, according to the Rascovsky and Gorno-Tempini criteria, were evaluated at a memory clinic in Buenos Aires, Argentina. Genomic DNA was obtained from peripheral blood leukocytes for all patients using standard protocols. C9ORF72 hexanucleotide repeat expansion (C9-HRE) was assessed by repeat-primed PCR. Whole exome sequencing and bioinformatic analysis of FTD-causative genes was performed on C9-HRE negative cases. 29 out of 43 patients (67%) were familial cases, of which 3 were C9-HRE positive (10.3%). Eleven familial cases who were C9-HRE negative were studied by exome sequencing. We found previously reported pathogenic variants in 2 cases [GRN (NM_002087.4): c.1216C>T: p.Gln406Ter and GRN (NM_002087.4): c.709-1G>A: p.?], respectively. Also, we found two variants of unknown significance in other two probands [PDE11A (NM_016953.4): c.2518G>A: p.Glu840Lys; PSEN2 (NM_000447.3): c.800T>G: p.Val267Gly], respectively. Here we report the genetic screening of familial FTD cases from a memory clinic in Argentina. C9-HRE is still the most common cause of familial FTD. Further studies are warranted on the role of the PSEN2 and PDE11A variants found in two probands. This work adds to the knowledge of the genetic landscape of FTD in our country.

INTRODUCTION Imaging biomarkers are fundamental in diagnosing neurodegenerative diseases, but their use in FTD remains limited. This study examines PET biomarkers in Argentine bvFTD patients. METHODS We studied a cohort of bvFTD patients (n = 20) and controls (n = 21) with three different PET radiotracers (18F‐FDG, 11C‐PiB, and 18F‐AV1451). RESULTS In bvFTD patients, 18F‐FDG PET showed significant hypometabolism in frontotemporal regions, along with hypermetabolism in the precentral gyrus, compared to normal controls. 11C‐PIB did not reveal a pattern typical of Alzheimer's disease, yet increased uptake was notably observed in the precentral region. We found 18F‐AV1451 uptake in frontal lobe, parietal, precuneus, cuneus, posterior cingulum, highly significant in bvFTD with respect to NCs. DISCUSSION PET biomarkers are a crucial tool in diverse real‐world clinical scenarios. However, their utility in revealing questions about the underlying pathology in FTD is still limited. Highlights First bvFTD study using 18F‐FDG, 11C‐PIB, and 18F‐AV1451 PET in a Latin American cohort. Frontotemporal hypometabolism with compensatory precentral hypermetabolism due to amyloid. Amyloid deposits observed in the precentral gyrus without an Alzheimer's‐like pattern. 18F‐AV1451 shows limitations in specificity for bvFTD pathology. Study provides new insights into PET biomarker utility for bvFTD clinical assessment.

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.

Background Genetic testing for individuals with dominantly inherited Alzheimer’s disease (DIAD) is now of greater relevance due to the existence of therapeutic trials available to this population. However, the impact and main drivers influencing the decision to seek genetic testing are relatively unknown in Latin America (LatAm). Here we present results from a regional genetic counseling and testing protocol implemented in LatAm. Method Our aim was to investigate the psychosocial impact of genetic testing in asymptomatic individuals from families with DIAD. A non‐randomized, controlled, prospective observational trial was conducted. Asymptomatic, first‐degree relatives of patients with DIAD from families with a presenilin 1, pathogenic variant (p.I416T or p.M146L) were interviewed before and after genetic testing. Group allocation was done according to participants’ choice (non‐randomized). Participants who received their genetic status (GS) were allocated to the test group, while those who opted out were allocated to the observational group. The primary outcome included change from baseline in depression, general anxiety, and health‐related anxiety in the test group relative to the observational group, using linear mixed effects models and chi‐squared tests. Result Forty‐five participants from Colombia and Argentina were invited and enrolled in the study. Thirty‐six individuals completed the genetic counseling sessions, and 25/36 (69.4%) learned their GS. Compared to families in Colombia, participants from Argentina were more likely to seek counseling and learn their GS (8/23, 34.9% vs, 17/20, 85.0%, respectively). Following genetic counseling, we found no significant differences between the group that learned their GS and those who did not learn their GS in anxiety (mean = 13.5, SD = 3.2 vs. 15.1, SD = 2.5, p = 0.2) or depression (mean = 5.4, SD = 2.3 vs. mean = 8.0, SD = 6.5, p = 0.6) scores. For both groups, anxiety and depression scores remained below cutoffs for clinical concern and without significant changes relative to baseline value levels. Conclusion Our pilot study shows that a structured genetic counseling and testing protocol for individuals at‐risk of DIAD is safe. We found relevant cross‐country differences in willingness to learn genetic status, which may reflect differences in religion, educational level, and urban vs rural areas, among others. Future studies should include larger cohorts and expand to other countries in LatAm.

Background Frontotemporal dementia (FTD) remains one of the most common forms of early‐onset dementia (45 to 65 years). FTD consists clinically and pathologically of a heterogeneous group of disorders characterized by progressive frontal and temporal lobe atrophy. Thirty to fifty percent of cases have a family history of the disease. In this work we aimed to characterize pathogenic variants implicated in familial FTD cases in a cohort from Argentina. Method A total of 43 patients (23 women, 20 men) meeting clinical criteria for probable behavioral variant‐FTD, semantic or nonfluent primary progressive aphasia, according to the Rascovsky and Gorno‐Tempini criteria, were evaluated at a memory clinic in Buenos Aires, Argentina. Genomic DNA was obtained from peripheral blood leukocytes for all patients using standard protocols. C9ORF72 hexanucleotide repeat expansion (C9‐HRE) was assessed by repeat‐primed PCR. Whole exome sequencing and bioinformatic analysis of FTD‐causative genes was performed on C9‐HRE negative cases. Result 29 out of 43 patients (67%) were familial cases, of which 3 were C9‐HRE positive (10.3%). Eleven familial cases who were C9‐HRE negative were studied by exome sequencing. We found previously reported pathogenic variants in 2 cases [GRN (NM₀02087.4): c.1216C>T: p.Gln406Ter and GRN (NM₀02087.4): c.709‐1G>A: p.?], respectively. Also, we found two variants of unknown significance in other two probands [PDE11A (NM₀16953.4): c.2518G>A: p.Glu840Lys; PSEN2 (NM₀00447.3): c.800T>G: p.Val267Gly], respectively. Conclusion Here we report the genetic screening of familial FTD cases from a memory clinic in Argentina. C9‐HRE is still the most common cause of familial FTD. Further studies are warranted on the role of the PSEN2 and PDE11A variants found in two probands. This work adds to the knowledge of the genetic landscape of FTD in our country.