Neuroimaging signatures of frailty: A population-based study in community-dwelling older adults (the Atahualpa Project).

AIMS: Frailty is a geriatric state of physical vulnerability that might be associated with cognitive decline in the absence of a concurrent neurodegenerative disorder. This assumes that neuroimaging studies are normal, but such examinations have rarely been considered for a frailty work-up. The present study identifies neuroimaging signatures in older adults interviewed with the Edmonton Frail Scale (EFS). METHODS: Community-dwellers aged ≥60 years enrolled in the Atahualpa Project were invited to undergo brain magnetic resonance imaging. Using generalized regression models, we evaluated the association between frailty and diffuse cortical and subcortical brain damage, after adjusting for relevant confounders. Multivariate models estimated the interaction of age in the association between frailty and these neuroimaging signatures. RESULTS: Out of 298 participants (mean age 70 ± 8 years, 57% women), 151 (51%) had moderate-to-severe cortical atrophy and 74 (25%) had moderate-to-severe white matter hyperintensities of presumed vascular origin. Mean EFS scores were 5 ± 3 points, with 140 (47%) individuals classified as robust, 65 (22%) as pre-frail and 93 (31%) as frail. Multivariate models showed a significant association between cortical atrophy with the continuous (P = 0.002) and the categorized (P = 0.008) EFS score. The relationship between white matter hyperintensities and the EFS was marginal. According to interaction models, prefrail or frail individuals aged ≥67 years presented more prominent neuroimaging signatures of diffuse cortical or subcortical damage than their robust counterparts. CONCLUSIONS: Neuroimaging signatures of frailty are mainly related to age. This reinforces the importance of early frailty detection to reduce its catastrophic consequences. Geriatr Gerontol Int 2017; 17: 270-276.

The Effect of Age in the Association between Frailty and Poor Sleep Quality: A Population-Based Study in Community-Dwellers (The Atahualpa Project).

PURPOSE: To assess the effect of age in the association between poor sleep quality and frailty status. DESIGN AND SETTING: Population-based, cross-sectional study conducted in Atahualpa, a rural village located in coastal Ecuador. METHODS: Out of 351 Atahualpa residents aged ≥ 60 years, 311 (89%) were interviewed with the Pittsburgh Sleep Quality Index (PSQI) and the Edmonton Frail Scale (EFS). The independent association between PSQI and EFS scores was evaluated by the use of a generalized linear model adjusted for relevant confounders. A contour plot with Shepard interpolation was constructed to assess the effect of age in this association. RESULTS: Mean score in the PSQI was 5 ± 2 points, with 34% individuals classified as poor sleepers. Mean score in the EFS was 5 ± 3 points, with 46% individuals classified as robust, 23% as prefrail, and 31% as frail. In the fully adjusted model, higher scores in the PSQI were significantly associated with higher scores in the EFS (ß 0.23; 95% CI 0.11-0.35; P < .0001). Several clusters depicted the strong effect of age in the association between PSQI and EFS scores. Older individuals were more likely to have high scores in the EFS and the PSQI, and younger individuals had low EFS scores and were good sleepers. Clusters of younger individuals who were poor sleepers and had high EFS scores accounted for the independent association between PSQI and EFS scores. CONCLUSIONS: This study shows the strong effect of age in the association between poor sleep quality and frailty status.

Evidence That Antibiotics Bind to Human Mitochondrial Ribosomal RNA Has Implications for Aminoglycoside Toxicity.

Aminoglycosides are a well known antibiotic family used to treat bacterial infections in humans and animals, but which can be toxic. By binding to the decoding site of helix44 of the small subunit RNA of the bacterial ribosome, the aminoglycoside antibiotics inhibit protein synthesis, cause misreading, or obstruct peptidyl-tRNA translocation. Although aminoglycosides bind helix69 of the bacterial large subunit RNA as well, little is known about their interaction with the homologous human helix69. To probe the role this binding event plays in toxicity, changes to thermal stability, base stacking, and conformation upon aminoglycoside binding to the human cytoplasmic helix69 were compared with those of the human mitochondrial and Escherichia coli helix69. Surprisingly, binding of gentamicin and kanamycin A to the chemically synthesized terminal hairpins of the human cytoplasmic, human mitochondrial, and E. coli helix69 revealed similar dissociation constants (1.3-1.7 and 4.0-5.4 µM, respectively). In addition, aminoglycoside binding enhanced conformational stability of the human mitochondrial helix69 by increasing base stacking. Proton one-dimensional and two-dimensional NMR suggested significant and specific conformational changes of human mitochondrial and E. coli helix69 upon aminoglycoside binding, as compared with human cytoplasmic helix69. The conformational changes and similar aminoglycoside binding affinities observed for human mitochondrial helix69 and E. coli helix69, as well as the increase in structural stability shown for the former, suggest that this binding event is important to understanding aminoglycoside toxicity.

A novel role of cytosolic protein synthesis inhibition in aminoglycoside ototoxicity.

Ototoxicity is a main dose-limiting factor in the clinical application of aminoglycoside antibiotics. Despite longstanding research efforts, our understanding of the mechanisms underlying aminoglycoside ototoxicity remains limited. Here we report the discovery of a novel stress pathway that contributes to aminoglycoside-induced hair cell degeneration. Modifying the previously developed bioorthogonal noncanonical amino acid tagging method, we used click chemistry to study the role of protein synthesis activity in aminoglycoside-induced hair cell stress. We demonstrate that aminoglycosides inhibit protein synthesis in hair cells and activate a signaling pathway similar to ribotoxic stress response, contributing to hair cell degeneration. The ability of a particular aminoglycoside to inhibit protein synthesis and to activate the c-Jun N-terminal kinase (JNK) pathway correlated well with its ototoxic potential. Finally, we report that a Food and Drug Administration-approved drug known to inhibit ribotoxic stress response also prevents JNK activation and improves hair cell survival, opening up novel strategies to prevent and treat aminoglycoside ototoxicity.