Brain clocks capture diversity and disparity in aging and dementia.

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of multimodal diversity (geographical, socioeconomic, sociodemographic, sex, neurodegeneration) on the brain age gap (BAG) is unknown. Here, we analyzed datasets from 5,306 participants across 15 countries (7 Latin American countries -LAC, 8 non-LAC). Based on higher-order interactions in brain signals, we developed a BAG deep learning architecture for functional magnetic resonance imaging (fMRI=2,953) and electroencephalography (EEG=2,353). The datasets comprised healthy controls, and individuals with mild cognitive impairment, Alzheimer's disease, and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (fMRI: MDE=5.60, RMSE=11.91; EEG: MDE=5.34, RMSE=9.82) compared to non-LAC, associated with frontoposterior networks. Structural socioeconomic inequality and other disparity-related factors (pollution, health disparities) were influential predictors of increased brain age gaps, especially in LAC (R2=0.37, F2=0.59, RMSE=6.9). A gradient of increasing BAG from controls to mild cognitive impairment to Alzheimer's disease was found. In LAC, we observed larger BAGs in females in control and Alzheimer's disease groups compared to respective males. Results were not explained by variations in signal quality, demographics, or acquisition methods. Findings provide a quantitative framework capturing the multimodal diversity of accelerated brain aging.

Brain clocks capture diversity and disparities in aging and dementia across geographically diverse populations.

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of diversity (including geographical, socioeconomic, sociodemographic, sex and neurodegeneration) on the brain-age gap is unknown. We analyzed datasets from 5,306 participants across 15 countries (7 Latin American and Caribbean countries (LAC) and 8 non-LAC countries). Based on higher-order interactions, we developed a brain-age gap deep learning architecture for functional magnetic resonance imaging (2,953) and electroencephalography (2,353). The datasets comprised healthy controls and individuals with mild cognitive impairment, Alzheimer disease and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (functional magnetic resonance imaging: mean directional error = 5.60, root mean square error (r.m.s.e.) = 11.91; electroencephalography: mean directional error = 5.34, r.m.s.e. = 9.82) associated with frontoposterior networks compared with non-LAC models. Structural socioeconomic inequality, pollution and health disparities were influential predictors of increased brain-age gaps, especially in LAC (R² = 0.37, F² = 0.59, r.m.s.e. = 6.9). An ascending brain-age gap from healthy controls to mild cognitive impairment to Alzheimer disease was found. In LAC, we observed larger brain-age gaps in females in control and Alzheimer disease groups compared with the respective males. The results were not explained by variations in signal quality, demographics or acquisition methods. These findings provide a quantitative framework capturing the diversity of accelerated brain aging.

Heterogeneous factors influence social cognition across diverse settings in brain health and age-related diseases.

Aging may diminish social cognition, which is crucial for interaction with others, and significant changes in this capacity can indicate pathological processes like dementia. However, the extent to which non-specific factors explain variability in social cognition performance, especially among older adults and in global settings, remains unknown. A computational approach assessed combined heterogeneous contributors to social cognition in a diverse sample of 1063 older adults from 9 countries. Support vector regressions predicted the performance in emotion recognition, mentalizing, and a total social cognition score from a combination of disparate factors, including clinical diagnosis (healthy controls, subjective cognitive complaints, mild cognitive impairment, Alzheimer's disease, behavioral variant frontotemporal dementia), demographics (sex, age, education, and country income as a proxy of socioeconomic status), cognition (cognitive and executive functions), structural brain reserve, and in-scanner motion artifacts. Cognitive and executive functions and educational level consistently emerged among the top predictors of social cognition across models. Such non-specific factors showed more substantial influence than diagnosis (dementia or cognitive decline) and brain reserve. Notably, age did not make a significant contribution when considering all predictors. While fMRI brain networks did not show predictive value, head movements significantly contributed to emotion recognition. Models explained between 28-44% of the variance in social cognition performance. Results challenge traditional interpretations of age-related decline, patient-control differences, and brain signatures of social cognition, emphasizing the role of heterogeneous factors. Findings advance our understanding of social cognition in brain health and disease, with implications for predictive models, assessments, and interventions.

Chronobiotic effect of melatonin in experimental optic neuritis.

Optic neuritis (ON) is an inflammatory condition of the optic nerve, which leads to retinal ganglion cell (RGC) loss. A subset of RGCs expressing the photopigment melanopsin regulates non-image-forming visual system (NIFVS) functions such as pupillary light reflex (PLR) and circadian rhythms. Melatonin is a chronobiotic agent able to regulate the circadian system. We analyzed the effect of ON on the NIFVS, and the effect of melatonin on the NIFVS alterations induced by ON. For this purpose, optic nerves from male Wistar rats received vehicle or bacterial lipopolysaccharide (LPS), and one group of animals received a subcutaneous pellet of melatonin or a sham procedure. The NIFVS was analyzed in terms of: i) blue light-evoked PLR, ii) the communication between the retina and the suprachiasmatic nuclei (by anterograde transport, and ex vivo magnetic resonance images), iii) locomotor activity rhythm, and iv) Brn3a(+) and melanopsin(+) RGC number (by immunohistochemistry). Experimental ON significantly decreased the blue light-evoked PLR, induced a misconnection between the retina and the suprachiasmatic nuclei, decreased Brn3a(+) RGCs, but not melanopsin(+) RGC number. A bilateral injection of LPS significantly increased the light (but not dark) phase locomotor activity, rhythm periodicity, and time of offset activity. Melatonin prevented the decrease in blue light-evoked PLR, and locomotor activity rhythm alterations induced by ON. These results support that ON provoked alterations of the circadian physiology, and that melatonin could restore the circadian system misalignment.

The "Use It or Lose It" Dogma in the Retina: Visual Stimulation Promotes Protection Against Retinal Ischemia.

Enriched environment (EE) protects the retina from adult rats against ischemia/reperfusion (I/R) injury; however, how the components of EE contribute to the recovery after retinal ischemic damage remains unclear. We analyzed the contribution of social, cognitive, and visual stimulation on functional and histological alterations induced by I/R. Male Wistar rats were submitted to unilateral ischemia by increasing intraocular pressure to 120 mmHg for 40 min. After ischemia, animals were housed in the following conditions: standard environment (SE), enriched environment (EE), novelty environment (NE), standard social environment (SoE), standard visual environment (SVE), or visual environment (VE). In another set of experiments, rats were submitted to bilateral ischemia and housed in SE or EE. At 2 weeks post-ischemia, rats were subjected to electroretinography and histological analysis. EE (but not SoE or NE) afforded functional and histological protection against unilateral ischemia. EE did not induce protection in animals submitted to bilateral ischemia. VE protected retinal function and histology and increased retinal BDNF levels, while a TrkB receptor antagonist prevented the protective effect of VE against I/R damage. In animals submitted to unilateral ischemia, EE and VE induced an increase in c-fos immunoreactivity in the ipsi and contralateral superior colliculus, whereas in animals submitted to bilateral ischemia, no changes in c-fos-immunoreactivity were observed in either superior colliculus from EE-housed animals. These results support that visual stimulation could be a potent stimulus for driving retinal protection in adult rats through a BDNF/TrkB-dependent mechanism, likely involving the superior colliculus.

Critical Role of Monocyte Recruitment in Optic Nerve Damage Induced by Experimental Optic Neuritis.

Neuroinflammatory diseases are characterized by blood-brain barrier disruption (BBB) and leukocyte infiltration. We investigated the involvement of monocyte recruitment in visual pathway damage provoked by primary optic neuritis (ON) induced by a microinjection of bacterial lipopolysaccharide (LPS) into the optic nerve from male Wistar rats. Increased Evans blue extravasation and cellularity were observed at 6 h post-LPS injection. In WT-GFPþ/WT chimeric rat optic nerves, the presence of GFP(+) neutrophils and GFP(+) monocytes, and in wild-type rat optic nerves, an increase in CD11b+CD45low and CD11b+CD45high cell number, were observed at 24 h post-LPS. Gamma-irradiation did not affect the increase in BBB permeability, but significantly lessened the decrease in pupil light reflex (PLR), and retinal ganglion cell (RGC) number induced by LPS. At 6 h post-LPS, an increase in chemokine (C-C motif) ligand 2 (CCL2) immunoreactivity co-localized with neutrophils (but not microglia/macrophages or astrocytes) was observed, while at 24 h post-injection, an increase in Iba-1-immunoreactivity and its co-localization with CCL2 became evident. The co-injection of LPS with bindarit (a CCL2 synthesis inhibitor) lessened the effect of LPS on PLR, and RGC loss. The treatment with etoposide or gadolinium chloride that significantly decreased peripheral monocyte (but not neutrophil or lymphocyte) percentage decreased the effect of LPS on PLR, and RGC number. Moreover, a negative correlation between PRL and monocyte (but not lymphocyte or neutrophil) percentage was observed at 7 days post-LPS. Taken together, these results support that monocytes are key players in the initial events that take place during primary ON.