Instituto de Neurociencia Biomédica

Background Cisplatin, an effective chemotherapy, is a cause of ototoxicity. It enters inner ear cells through Organic Cation Transporter 2 (OCT2). Recently, we identified another cochlear transporter, Multidrug and Toxin Extrusion Protein 1 (MATE1); it allows cisplatin efflux in renal cells. OCT2 and MATE1 appear to work together in eliminating renal toxins. 4-aminopyridine (4-AP), a known blocker of voltage-dependent K+ channels, blocks OCT2 but not MATE1 in the kidney. We hypothesize that 4-AP could prevent cisplatin from entering cochlear cells, without inhibiting the efflux of cisplatin that may have already entered. This could enhance clearance, mitigating ototoxicity. Objective Determine the otoprotective potential of 4-AP in vitro following cisplatin exposure. Methods Mice cochlear explants were treated with cisplatin (20 μM), with or without 4-AP (500 μM) for 24 h, evaluated for caspase 3/7 activity with Cell Event ® , visualized with confocal and phase contrast microscopy. Moreover, HeLa cells and cochlear explants were exposed to cisplatin (75 μM and 30 μM, respectively) with or without 4-AP in the explants and were evaluated for cisplatin-DNA adducts and cleaved caspase-3 immunohistochemistry. Results For cochlear explants exposed to cisplatin, Cell Event ® staining occurred in the supporting cells, medial to the hair cells, and in the organ of Corti. No significant differences were found between cisplatin-exposed explants with or without 4-AP. In HeLa cells, consistent cellular staining for cisplatin-DNA adducts and cleaved caspase-3 was observed. However, this was not seen in cochlear explants, and there was no significant decrease in staining levels with 4-AP co-treatment. Conclusions In this in vitro study, no otoprotective potential of 4-AP against cisplatin-induced ototoxicity was observed. While 4-AP blocks OCT2, it did not decrease cisplatin-DNA adducts in cochlear cells. Further research into OCT2 and MATE1 transport mechanisms is needed.

The regenerative potential of developing cortical axons depends on intrinsic mechanisms, such as axon-autonomous protein synthesis, that are still not fully understood. An emerging factor in this regenerative response is the bidirectional interplay between microtubule dynamics and the axonal ER. We hypothesize that locally synthesized ER proteins regulate microtubule dynamics and the regeneration of cortical axons. RNA data mining identified the ER-shaping protein Reticulon-1 as a relevant candidate across eight axonal transcriptomes. Using microfluidics, we show that axonal treatment with a small RNA against Reticulon-1 mRNA (Reticulon-1 knockdown) increases outgrowth of injured cortical axons while reducing their tubulin levels. We show by live-cell imaging that axonal Reticulon-1 knockdown increases microtubule growth rate in noninjured axons and restores this parameter after injury. Axonal inhibition of the microtubule-severing protein Spastin prevents the effects of Reticulon-1 knockdown over tubulin levels and outgrowth. We provide evidence that the Reticulon-1C isoform is synthesized within axons and attenuates Spastin-mediated microtubule severing. These findings support a model in which axonal protein synthesis regulates microtubule dynamics and axon outgrowth after injury.

BackgroundFunctional ability is a key indicator of cognitive health, distinguishing cognitively unimpaired (CU) aging, mild cognitive impairment (MCI), and dementia. However, sociocultural factors such as gender roles, education, and age‐related differences influence activity participation, complicating assessments. The Activities of Daily Living Questionnaire‐Technologies (T‐ADLQ) evaluates three domains of functional ability: instrumental activities of daily living (iADL), basic activities of daily living (bADL), and advanced activities of daily living (aADL). It includes a response option, “Never did this activity/Don't know” (ND/DK), which may reflect disparities unrelated to cognitive impairment.MethodThis study analyzed ND/DK responses in the GERO cohort, a prospective study in Santiago, Chile, following 291 dementia‐free older adults with cognitive complaints (≥70 years) for three years to assess cognitive, functional, psychosocial, and medical factors. We examined how gender, education, and age influenced functional ability assessments using a test for equality of proportions to compare ND/DK response distributions.ResultMen were significantly more likely to report never engaging in household tasks such as taking pills (4.1% vs. 0.5%, p = 0.0049), cooking (24.5% vs. 1.0%, p <0.001), housekeeping (10.2% vs. 1.0%, p = 0.0004), and laundry (53.1% vs. 1.9%, p <0.001). Conversely, women had higher ND/DK responses in home repairs (42.0% vs. 19.1%, p = 0.0029), employment (23.2% vs. 6.1%, p = 0.0071), driving (72.5% vs. 20.4%, p <0.001), and ATM usage (58.0% vs. 34.7%, p = 0.0033). Participants with <6 years of education had significantly higher ND/DK responses in financial management (9.4% vs. 3.0%, p = 0.0393), driving (83.0% vs. 56.9%, p = 0.0003), and technology use (computer access: 84.9% vs. 61.4%, p = 0.0013; email access: 96.2% vs. 68.8%, p <0.001). Individuals aged ≥80 showed higher ND/DK rates in home maintenance (7.7% vs. 1.6%, p = 0.0147), mobile phone use (33.9% vs. 13.7%, p = 0.0003), and internet access (78.5% vs. 57.4%, p = 0.0024).ConclusionSociocultural factors strongly influence functional ability assessments, with notable disparities by gender, education, and age. These findings highlight the need to interpret ND/DK responses carefully to prevent misclassification of functional impairment in cognitive aging evaluations. Additionally, improving assessment tools to account for sociocultural variations is essential for more accurate evaluations.

BackgroundFunctional impairment (FI) is a key component in diagnosing and monitoring the severity of neurodegenerative dementia (ND). It manifests in several dimensions, such as everyday cognition, mobility, social functioning, and activities of daily living (ADLs). However, traditional assessments have primarily focused on ADLs, often neglecting the other dimensions of functional phenotype.This study aims to assess the utility of the Chilean multidimensional functional assessment (Ch‐MFA, see Figure 1), including ADLs, social behavior, mobility, and everyday cognition in differentiating Alzheimer's disease (AD) and frontotemporal dementia (FTD), and to predict their severity measured in the Clinical Dementia Rating (CDR).Method308 patients were recruited in Peru, comprising 209 controls, 44 FTD, and 55 AD. Functional assessments include ADL (T‐ADLQ, DAD‐E), social behavior Blessed Dementia Rating Scale (BDR), mobility (WHODAS), everyday cognition (ECog), and CDR for severity. Data was normalized for each assessment, and groups were stratified regarding age and educational level, obtaining 72 controls, 24 FTD, and 45 AD for the predictive analysis. Random Forest (RF) models were trained using 70% of the data, while 30% was reserved for testing the prediction. Cross‐validation (20‐fold) and feature selection were used to reduce overfitting and identify a simpler set of questions.ResultThe Ch‐MFA indicates a 0.81 ± 0.03 average f1‐score when differentiating the group (control, FTD, and AD), which is 0.12 ± 0.10 better than the best‐performing unidimensional assessment (T‐ADLQ) with only 14 questions (4 T‐ADLQ, 2 BDR, 4 ECog and 3 WHODAS). As for the severity, Ch‐MFA shows a 0.65 ± 0.17 average f1‐score when differentiating severities of 0.5, 1, and 2, increasing to 0.88 ± 0.06 when it's only between 1 and 2 with a total of 4 questions (2 T‐ADLQ, 2 ECog). See Figure 2.ConclusionOur results show that the Ch‐MFA achieves better results than a unidimensional assessment. Interestingly, functional dimensions that distinguish types of dementia differed from those that predict their severity. Our results suggest that a multidimensional phenotype may better reflect the specificity of dementia subtypes.

BackgroundThe digit span task, a measure of auditory verbal short‐term and working memory, is widely used globally. Emerging research has revealed variations in digit span performance across languages among young adults; however, studies focusing on older populations are scarce and typically involving limited languages. This study investigates digit span performance among older adults (40‐90 year‐old) across fourteen languages and explored the influence of lexical and numerical properties on cognitive assessment.MethodWe examined digit span performance among cognitively normal participants (CN), individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) across fourteen language cohorts totalling 3,681 participants: English (n = 446), Mandarin (n = 97), Cantonese (n = 65), Spanish (n = 218), Kannada (n = 69), Hindi (n = 72), Telugu (n = 69), Malayalam (n = 70), Bengali (n = 70), French (n = 299), Korean (n = 1098), Italian (n = 540), Arabic (n = 50), and Turkish (n = 518). First, we analyzed language differences in digit span performance among CN using ANOVA and general linear models. We then conducted Receiver operating characteristic (ROC) analyses to identify the optimal cutoff values for AD. Next, we computed the digit count, syllable count, and numerical magnitude (i.e. the average sum of the digits) of all digit stimuli in the English cohort and analyzed their effects via linear and ridge regression analyses.ResultThe forward (FDS) and backward digit span (BDS) tests revealed significant differences among CN across the fourteen language cohorts even after adjusting for age and education (FDS:F=38.62, p <0.001; BDS:F=19.23, p <0.001). ROC analysis revealed varying optimal cutoff values across languages: English (FDS:6, BDS:4), Italian and Turkish (FDS:5, BDS:4), Mandarin (FDS:7, BDS:5), Cantonese (FDS:7, BDS:4), and French (FDS:6, BDS:3). Further analysis indicated that the interaction between digit and syllable counts significantly impacted FDS accuracy in English speakers (linear:p=0.00035; ridge:p< 0.000001), with no significant effect from digit count alone after adjusting for interaction. Conversely, BDS performance showed a significant negative influence from digit count (p = 0.00858), with numerical magnitude and syllable count nearing significance (p = 0.083 and p = 0.066, respectively).ConclusionVariations in digit span performance across languages illustrate the role of linguistic and numerical factors in cognitive assessments, even with tests targeting non‐language domains using digit stimuli. These findings underscore the critical value of language diversity in cognitive research.

BackgroundFunctional impairment (FI) in activities of daily living (ADL) is a critical criterion for diagnosing dementia that could be categorized into its three dimensions: basic (BADL), instrumental (IADL) and advanced activities (aADL). While FI has been well studied in Alzheimer's disease (AD), this characterization has been underexplored in frontotemporal dementia (FTD) and even more in Latin American countries, where genetic and exposome diversity defines variability in its clinical presentation.MethodWe evaluated 547 individuals from RedLat consortium for dementia research in Latin America (262 controls, 236 AD and 49 FTD) from 5 Latin American countries (Argentina, Brazil, Chile, Colombia and Mexico). We performed descriptive statistics for sociodemographic variables. Functional performance was evaluated through the Tecnology‐Activities of Daily Living (T‐ADLQ) global score and subscores for BADL, IADL, and aADL. Kruskal‐Wallis and Dunn post‐hoc tests were performed to compare T‐ADLQ scores between the three groups.ResultAD participants showed poor global cognitive performance compared to FTD, and FTD presented higher scores in NPI than AD. In total, basic, instrumental, and advanced T‐ADLQ scores, FTD showed higher scores than AD participants, which means poor functional performance in FTD participants; however, these differences only showed significance in the basic domain.ConclusionIn Latin American individuals, FTD showed poorer functional performance than AD patients, statistically significant in the basic domain. Further research would be oriented toward exploring the relationship between this functional performance and cognitive and clinical symptoms to determine the functional profile in FTD, compared with AD.

BackgroundWith increasing life expectancy, aging‐related neurocognitive challenges are becoming more prevalent worldwide. A continuum of severity, from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) and Alzheimer's disease dementia (ADD), is measurable through cognitive and neuroimaging assessments. However, these approaches are costly, subject to scheduling delays, and reliant on specialized personnel or resources, which are scarce in many regions. Automated speech and language analysis (ASLA) offers an affordable, scalable solution for detecting neurocognitive compromise in underserved areas. Yet, no prior study has employed ASLA to predict neuropsychological and brain measures across this continuum in Spanish‐speaking Latinos. Our study addresses this gap.MethodWe recruited 150 Chilean individuals with diverse cognitive profiles: 17 healthy controls, 55 with SCD, 57 with MCI, and 21 with ADD. Participants completed 1‐minute phonemic and semantic fluency tasks, alongside cognitive (Addenbrooke's Cognitive Examination‐III [ACE‐III], Montreal Cognitive Assessment [MoCA]) and executive function (INECO Frontal Screening [IFS]) tests and MRI scans. Machine learning models were trained with word‐property and speech‐timing features from fluency responses (both separate and combined), derived via the TELL app, to predict cognitive test outcomes, total gray matter (GM) and white matter volumes, hippocampal GM volume, and a mask encompassing ADD‐sensitive regions. The best regressors were selected based on the 95% confidence intervals of R2 scores. Pearson's partial correlations between actual and predicted values were computed, controlling for age, sex, and education (and MoCA scores for brain‐related measures). Analyses were repeated for each fluency task, their combination, and their average.ResultsSignificant partial Pearson correlations were obtained for ACE‐III (r = .55, p < .001), MoCA (r = .39, p < .001), and IFS (r = .31, p = .001) scores, as well as for normalized GM volume (r = .34, p = .006). All results correspond to word‐property features, with combined fluency tasks.ConclusionA fully automated, multivariate pipeline captures cognitive and MRI measures of brain health based on brief fluency tasks. Unlike gold‐standard tests, this approach is examiner‐independent, objective, time‐efficient, and affordable. This approach represents a scalable resource to favor equity in the global fight against dementia and cognitive decline.

Tinnitus is the perception of sounds without external stimuli, affecting 10%-15% of the general population and up to 25% of individuals over 70 years of age. While traditionally viewed as an auditory phenomenon, growing evidence highlights the role of the central nervous system in its pathophysiology. One of the proposed mechanisms, the “gating hypothesis” of tinnitus, suggests an alteration in the modulation of sensory activity by the frontostriatal network. Although structural changes in frontal areas support this idea, gray matter differences in subcortical regions—such as the auditory pathway and basal ganglia—remain poorly understood. Here, we examined subcortical structures and auditory function in older adults with mild presbycusis from the ANDES cohort, including 51 tinnitus patients and 40 age-matched controls. We analyzed brain volume via structural magnetic resonance imaging and subcortical auditory functionality via auditory brainstem responses (ABRs). We found non-significant differences in age, hearing loss, cognitive impairment, and ABR amplitudes between the groups. Notably, tinnitus patients presented a significant increase in the volume of basal ganglia structures (striatum and pallidum) but not in auditory areas. These findings reinforce the role of the basal ganglia in age-related tinnitus pathophysiology.

The gut-brain axis enables communication between the central nervous system and the gut, with certain microbial metabolites influencing neurodegeneration. Using genome-scale metabolic modeling, we designed and tested a synthetic microbial consortium with predicted capacity to produce GABA and other neurometabolites in a Drosophila melanogaster model of neurodegeneration of Parkinson's Disease (PD). The consortium (Levilactobacillus brevis, Lacticaseibacillus paracasei, Bacteroides thetaiotaomicron) produced GABA in bioreactors. Female PD flies receiving the consortium exhibited protection from locomotor impairment at 10 and 25 days upon consortium administration. Head metabolomics revealed partial restoration of PD-associated alterations in energy balance, amino acid and neurotransmitter metabolism, and disease-related biomarkers. Early administration increased microbiome diversity and Lactobacillus abundance. These findings suggest that rationally designed microbial consortia targeting neurometabolite production can modulate brain physiology and confer neuroprotection, supporting their potential for microbiome-based interventions in neurodegenerative disease.