Attenuation of Age-Related Hearing Impairment in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice Treated with Fatty Acid Synthase Inhibitor CMS121.

In the senescence-accelerated mouse prone 8 (SAMP8) mouse model, oxidative stress leads to premature senescence and age-related hearing impairment (ARHI). CMS121 inhibits oxytosis/ferroptosis by targeting fatty acid synthase. The aim of our study was to determine whether CMS121 is protective against ARHI in SAMP8 mice. Auditory brainstem responses (ABRs) were used to assess baseline hearing in sixteen 4-week-old female SAMP8 mice, which were divided into two cohorts. The control group was fed a vehicle diet, while the experimental group was fed a diet containing CMS121. ABRs were measured until 13 weeks of age. Cochlear immunohistochemistry was performed to analyze the number of paired ribbon-receptor synapses per inner hair cell (IHC). Descriptive statistics are provided with mean ± SEM. Two-sample t-tests were performed to compare hearing thresholds and paired synapse count across the two groups, with alpha = 0.05. Baseline hearing thresholds in the control group were statistically similar to those of the CMS121 group. At 13 weeks of age, the control group had significantly worse hearing thresholds at 12 kHz (56.5 vs. 39.8, p = 0.044) and 16 kHz (64.8 vs. 43.8, p = 0.040) compared to the CMS121 group. Immunohistochemistry showed a significantly lower synapse count per IHC in the control group (15.7) compared to the CMS121 group (18.4), p = 0.014. Our study shows a significant reduction in ABR threshold shifts and increased preservation of IHC ribbon synapses in the mid-range frequencies among mice treated with CMS121 compared to untreated mice.

Audiometric Findings in Senior Adults of 80 Years and Older.

Objective: To examine hearing thresholds in senior adults of 80 years and older and compare this data to the current ISO 7029 reference values. Design: A descriptive, prospective study testing pure-tone and speech audiometry in senior adults participating in the BUTTERFLY study or the BrUssels sTudy on The Early pRedictors of FraiLtY. A Gerontological study to identify determinants for active aging and for early stages of frailty in the oldest population. Using the formula given by ISO 7028:2017 the median value of hearing was calculated based on the sex and age of the participant and compared to the measured hearing thresholds. Results: 151 senior adults were included. The prevalence of hearing loss was 90.7% (PTA > 20 dB HL). The results were compared to the mean ISO values, calculated for every participant. Both males and females in our study population had worse hearing thresholds than could be expected based on the ISO reference values. In our study population with moderate hearing loss (PTA > 40 dB HL), 38% is underserved in term of hearing restoration healthcare and yet another 38% is unsatisfied with the result of the hearing aids. Given the vast impact on the individual and society, this is a problem in need of our attention. Conclusion: The ISO 7029 reference values may be an underestimation of hearing loss in senior adults of 80 years and older. Therefore we present a statistical distribution of hearing thresholds on different frequencies related to age and sex that can be used as a baseline for further development of the reference values.

Olfactory, Auditory, and Vestibular Performance: Multisensory Impairment Is Significantly Associated With Incident Cognitive Impairment.

Background: Dysfunction in the olfactory, auditory, and vestibular systems are commonly seen in aging and are associated with dementia. The impact of sensory loss(es) on cognition is not well understood. Our aim was to assess the relationships between performance on objective multisensory testing and quantify the impact of dysfunction on cognition. Methods: Patients presenting with subjective hearing loss presenting to a tertiary care otologic/audiologic clinic were identified and underwent multisensory testing using the Affordable, Rapid Olfactory Measurement Array (AROMA), pure tone audiometric evaluations, and the Timed "Up and Go" test. Cognitive impairment (CI) was assessed via the Montreal Cognitive Assessment (MoCA) was also administered. Key Results: 180 patients were enrolled. Thirty one percentage (n = 57) screened positive for cognitive impairment. When evaluating single sensory impairments, we found that olfactory dysfunction, gait impairment, and sensorineural hearing loss were all statistically significantly (p < 0.05) associated with a higher risk of cognitive impairment (ORs 3.89, 3.49, and 2.78, respectively) for CI. Multisensory impairment was significantly associated with cognitive impairment. Subjects with dysfunction in all domains were at the highest risk for cognitive impairment (OR 15.7, p < 0.001) vs. those with impairment in 2 domains (OR 5.32, p < 0.001). Conclusion: Dysfunction of the olfactory, auditory, and vestibular systems is associated with a significantly increased risk of CI. The dramatically increased risk of CI with multisensory dysfunction in all three systems indicated that MSD may synergistically contribute to CI.

Association between NR3C1 gene polymorphisms and age-related hearing impairment in Qingdao Chinese elderly.

BACKGROUND: Age-related hearing impairment (ARHI) has attracted increasing attention recently. It is caused by genetic and environmental factors. A number of ARHI-related genes have been found. This study aimed to detect the potential association between NR3C1 gene polymorphisms and ARHI by means of weighted allele score. METHODS: A total of 861 participants from Qingdao city were selected by means of cluster random sampling. We statistically evaluated the characteristics of individuals and used the Mann-Whitney U test or chi-square test for comparison. The publicly available expression quantitative trait locus (eQTL) was queried on the website of the Genotype-Tissue Expression (GTEx). We used the weighted allele score and logistic regression analysis to explore the association between NR3C1 gene polymorphisms and ARHI. Finally, the prediction model was constructed by logistic regression and receiver operating characteristic (ROC) curve. RESULTS: All individuals over 60 years of age were enrolled in this study. The allele of rs61757411, rs41423247 and rs6877893 were significantly different between the ARHI group and the normal hearing group (P < 0.01). Though eQTL analysis, rs6877893 and rs33388 might affect the occurrence of ARHI by affecting the expression of NR3C1 gene in artery aorta. Then we performed two models: one without adding any covariates into model and the other adjusting for demographic characteristic, smoking and drinking, diet and exercise, and physical conditions. In the multivariate-adjusted model 2, the odds ratio with 95% confidence interval for weighted allele score (NR3C1) was 0.841 (0.710-0.995, P = 0.043). The area under the ROC curve was 0.755, indicating that the model had good predictability. CONCLUSIONS: Our study suggests that NR3C1 gene polymorphisms was significantly associated with ARHI.

The association of heat shock protein genetic polymorphisms with age-related hearing impairment in Taiwan.

BACKGROUND: Age-related hearing impairment (ARHI) is a major disability among the elderly population. Heat shock proteins (HSPs) were found to be associated with ARHI in animal studies. The aim of this study was to analyze the associations of single nucleotide polymorphisms (SNPs) of HSP genes with ARHI in an elderly population in Taiwan. METHODS: Participants ≥65 years of age were recruited for audiometric tests and genetic analyses. The pure tone average (PTA) of the better hearing ear was calculated for ARHI evaluation. The associations of HSPA1L (rs2075800 and rs2227956), HSPA1A (rs1043618) and HSPA1B (rs2763979) with ARHI were analyzed in 146 ARHI-susceptible (cases) and 146 ARHI-resistant (controls) participants. RESULTS: The "T" allele of HSPA1B rs2763979 showed a decreased risk of ARHI. The "TT" genotype of rs2763979 also showed a decreased risk of ARHI in the dominant hereditary model. For HSPA1L (rs2075800 and rs2227956) and HSPA1A (rs1043618), the haplotype "CAG" was related to a decreased risk of ARHI. CONCLUSION: These findings suggest that HSP70 polymorphisms are associated with susceptibility to ARHI in the elderly population.

A Multi-Institutional Study of Older Hearing Aids Beginners-A Prospective Single-Arm Observation on Executive Function and Social Interaction.

OBJECTIVES: To obtain new insights into research questions on how executive function and social interaction would be observed to change after the introduction of hearing aids (HAs) in older people with hearing impairment. DESIGN: Multi-institutional prospective single-arm observational study. SETTING AND PARTICIPANTS: Outpatients with complaints of hearing difficulty who visited HA clinics between October 18, 2017, and June 30, 2019, in 7 different university hospitals in Japan. METHODS: The inclusion criteria of the study named Hearing-Aid Introduction for Hearing-Impaired Seniors to Realize a Productive Aging Society-A Study Focusing on Executive Function and Social Activities Study (HA-ProA study) were age ≥60 years and no history of HA use. A series of multi-institution common evaluations including audiometric measurements, the digit symbol substitution test to assess executive functions, convoy model as an index of social relations, and hearing handicap inventory for the elderly (HHIE) were performed before (pre-HA) and after 6 months of the HA introduction (post-HA). RESULTS: Out of 127 enrollments, 94 participants completed a 6-month follow-up, with a mean age of 76.9 years. The digit symbol substitution test score improved significantly from 44.7 at baseline to 46.1 at 6 months (P = .0106). In the convoy model, the social network size indicated by the number of persons in each and whole circles were not significantly different between pre- and post-HA; however, the total count for kin was significantly increased (P = .0344). In the analyses of HHIE, the items regarding the family and relatives showed significant improvement. CONCLUSIONS AND IMPLICATIONS: HA use could benefit older individuals beginning to use HAs in executive function and social interaction, though the results should be interpreted cautiously given methodological limitations such as a single-arm short 6 months observation. Reduction in daily hearing impairment would have a favorable effect on relationships with the family.

Independent risk factors for acute hospital patients' reduced ability to hear electronic axillary thermometer alarms.

AIM: Hearing loss prevalence increases dramatically with age. However, no prior studies exist regarding the prevalence and factors related to reduced ability to hear alarm sounds using electronic axillary thermometers. This study aimed to investigate the number of individuals with a reduced ability to hear the alarm sound of the electronic axillary thermometers among participants over 20 and 65 years old (Objective 1) and to identify the factors associated with reduced ability to hear the alarm sound (Objective 2). METHODS: In this 5-month cross-sectional study, the participants, aged ≥20 years, were recruited from samples of patients at an acute hospital. The outcome measured was the average number of seconds for each participant between the axillary placement of a thermometer tip and their report of hearing the alarm, performed three times per patient. RESULTS: Complete data were obtained from 107 participants, with 58 (54.2%) showing a reduced ability to hear the alarm. The prevalence of reduced ability to hear the alarm was 69.5% (>65 years older). Multivariate analysis demonstrated that age was the factor most significantly associated with reduced hearing ability. Age 70 was determined as the cut-off point for ability to hear the alarm. CONCLUSIONS: This is a serious issue, as many individuals with the inability to hear the alarm sound use the electronic axillary thermometer with the alarm sound. For a reliable measurement of body temperature, digital thermometers need alternative alarm signals, (e.g., vibration) for self-use by adults ≥70 years to correctly measure body temperature.

Osteoporosis and hearing loss: findings from the Korea National Health and Nutrition Examination Survey 2009-2011 / Osteoporose e perda auditiva: resultados da Pesquisa Nacional do Exame de Saúde e Nutrição da Coreia de 2009 a 2011

Abstract Introduction: Age-related hearing impairment is the most common sensory dysfunction in older adults. In osteoporosis, the mass of the ossicles will be decreased, affecting the bone density of the cochlea, and interfering with the sound transmission to the cochlea. Age related hearing loss might be closely related to osteoporosis. Objective: To determine the relationship between age-related hearing impairment and osteoporosis by investigating the relationship between hearing loss and cortical bone density evaluated from femur neck bone mineral density. Methods: We used data from the Korea National Health and Nutrition Examination Survey to examine the associations between osteoporosis and age-related hearing impairment from 2009 to 2011. Total number of participants was 4861 including 2273 men and 2588 women aged 50 years or older. Osteoporosis was defined as a bone mineral density 2.5 standard deviations below according to the World Health Organization diagnostic classification. Age-related hearing impairment was defined as the pure-tone averages of test frequencies 0.5, 1, 2, and 4 kHz at a threshold of 40 dB or higher on the more impaired hearing side. Results: Total femur T-score (p < 0.001), lumbar-spine T-score (p < 0.001) and, femur neck T-score (p < 0.001) were significantly lower in the osteoporosis group compared to the normal group. Thresholds of pure-tone averages were significantly different in normal compared to osteopenia, and osteoporosis groups. In addition, there were significantly higher pure-tone averages thresholds in the osteoporosis group compared to other groups (p < 0.001). After adjusting for all covariates, the odds ratio for hearing loss was significantly increased by 1.7 fold with reduced femur neck bone mineral density (p < 0.01). However, lumbar spine bone mineral density was not statistically associated with hearing loss (p = 0.22). Conclusion: Our results suggest that osteoporosis is significantly associated with a risk of hearing loss. In addition, femur neck bone mineral density was significantly correlated with hearing loss, but lumbar spine bone mineral density was not.

Resumo Introdução: A perda auditiva associada ao envelhecimento é a disfunção sensorial mais comum em idosos. Na osteoporose, a massa dos ossículos diminui e afeta a densidade óssea da cóclea, o que irá interferir na transmissão do som para a mesma. A perda auditiva associada à idade pode estar intimamente relacionada à osteoporose. Objetivo: Determinar a relação entre deficiência auditiva relacionada à idade e osteoporose, investigar a relação entre perda auditiva e densidade óssea cortical avaliada a partir da densidade mineral óssea do colo do fêmur. Método: Utilizamos dados da Korea National Health and Nutrition Examination Survey para examinar as associações entre osteoporose e perda auditiva associada ao envelhecimento de 2009 a 2011. O número total de participantes foi de 4.861, incluiu 2.273 homens e 2.588 mulheres com 50 anos ou mais. A osteoporose foi definida como densidade mineral óssea com 2,5 desvios-padrão abaixo da média, de acordo com a classificação diagnóstica da Organização Mundial da Saúde. A perda auditiva associada ao envelhecimento foi definida como as médias de tom puro das frequências de teste de 0,5, 1, 2 e 4 kHz a um limiar de 40 dB ou superior no lado da audição mais afetado. Resultados: O T-score total do fêmur (p < 0,001), o T-score da coluna lombar (p < 0,001) e o T-score do colo do fêmur (p < 0,001) foram significantemente menores no grupo com osteoporose em comparação ao grupo normal. Os limiares de médias de tom puro foram significantemente diferentes nos grupos normais em comparação com aqueles com osteopenia e osteoporose. Além disso, houve limiares significantemente maiores de médias de tom puro no grupo com osteoporose em comparação com os outros grupos (p < 0,001). Após o ajuste para todas as covariáveis, a odds ratio da perda auditiva mostrou estar significantemente aumentada em 1,7 vez com densidade mineral óssea reduzida no colo do fêmur (p < 0,01). No entanto, a densidade mineral óssea da coluna L não se associou estatisticamente à perda auditiva (p = 0,22). Conclusão: Nossos resultados sugerem que a osteoporose está significantemente associada ao risco de perda auditiva. Além disso, a densidade mineral óssea da coluna lombar não se correlacionou com a perda auditiva, apenas a densidade mineral óssea do colo do fêmur foi significantemente correlacionada.

Evidence for independent peripheral and central age-related hearing impairment.

Deleterious age-related changes in the central auditory nervous system have been referred to as central age-related hearing impairment (ARHI) or central presbycusis. Central ARHI is often assumed to be the consequence of peripheral ARHI. However, it is possible that certain aspects of central ARHI are independent from peripheral ARHI. A confirmation of this possibility could lead to significant improvements in current rehabilitation practices. The major difficulty in addressing this issue arises from confounding factors, such as other age-related changes in both the cochlea and central non-auditory brain structures. Because gap detection is a common measure of central auditory temporal processing, and gap detection thresholds are less influenced by changes in other brain functions such as learning and memory, we investigated the potential relationship between age-related peripheral hearing loss (i.e., audiograms) and age-related changes in gap detection. Consistent with previous studies, a significant difference was found for gap detection thresholds between young and older adults. However, among older adults, no significant associations were observed between gap detection ability and several other independent variables including the pure tone audiogram average, the Wechsler Adult Intelligence Scale-Vocabulary score, gender, and age. Statistical analyses showed little or no contributions from these independent variables to gap detection thresholds. Thus, our data indicate that age-related decline in central temporal processing is largely independent of peripheral ARHI.

The association of genetic polymorphisms in interleukin-1 receptors type 1 and type 2 with age-related hearing impairment in a Taiwanese population: a case control study.

BACKGROUND: Age-related hearing impairment (ARHI) is a major disability among the elder population. Chronic inflammation is an important factor in the development of ARHI. Interleukin-1 (IL-1) plays a key role in inflammation and may be associated with ARHI. The aim of this study is to analyze the associations of single nucleotide polymorphisms (SNPs) of IL-1 receptor genes with ARHI in an elderly population in Taiwan. METHOD: Participants ≥65 years of age were recruited for audiometric tests and genetic analyses. The bilateral pure-tone average (PTA) of high-tone hearing levels was calculated for ARHI evaluation. The associations of SNPs of the IL-1 receptor type 1 gene (IL1R1) (rs3917225 and rs2234650) and type 2 gene (IL1R2) (rs4141134 and rs2071008) with ARHI were analyzed in 182 ARHI-susceptible (case) and 176 ARHI-resistant (control) participants. RESULTS: The G allele of IL1R1 rs3917225 showed a decreased risk of ARHI after adjustments for sex, age, and noise exposure. The GG genotype of IL1R1 rs3917225 in all hereditary models and the TT genotype of IL1R2 rs2071008 in the recessive model also showed decreased risks of ARHI after adjustments. CONCLUSION: These findings suggest that IL1R1 and IL1R2 polymorphisms may contribute to the decreased risk of ARHI in the elderly population.

Osteoporosis and hearing loss: findings from the Korea National Health and Nutrition Examination Survey 2009-2011.

INTRODUCTION: Age-related hearing impairment is the most common sensory dysfunction in older adults. In osteoporosis, the mass of the ossicles will be decreased, affecting the bone density of the cochlea, and interfering with the sound transmission to the cochlea. Age related hearing loss might be closely related to osteoporosis. OBJECTIVE: To determine the relationship between age-related hearing impairment and osteoporosis by investigating the relationship between hearing loss and cortical bone density evaluated from femur neck bone mineral density. METHODS: We used data from the Korea National Health and Nutrition Examination Survey to examine the associations between osteoporosis and age-related hearing impairment from 2009 to 2011. Total number of participants was 4861 including 2273 men and 2588 women aged 50 years or older. Osteoporosis was defined as a bone mineral density 2.5 standard deviations below according to the World Health Organization diagnostic classification. Age-related hearing impairment was defined as the pure-tone averages of test frequencies 0.5, 1, 2, and 4kHz at a threshold of 40dB or higher on the more impaired hearing side. RESULTS: Total femur T-score (p<0.001), lumbar-spine T-score (p<0.001) and, femur neck T-score (p<0.001) were significantly lower in the osteoporosis group compared to the normal group. Thresholds of pure-tone averages were significantly different in normal compared to osteopenia, and osteoporosis groups. In addition, there were significantly higher pure-tone averages thresholds in the osteoporosis group compared to other groups (p<0.001). After adjusting for all covariates, the odds ratio for hearing loss was significantly increased by 1.7 fold with reduced femur neck bone mineral density (p<0.01). However, lumbar spine bone mineral density was not statistically associated with hearing loss (p=0.22). CONCLUSION: Our results suggest that osteoporosis is significantly associated with a risk of hearing loss. In addition, femur neck bone mineral density was significantly correlated with hearing loss, but lumbar spine bone mineral density was not.

Quantitative criteria for age-related hearing loss using audiometric configuration analysis.

OBJECTIVES: To suggest the most adaptable criteria of age-related hearing loss (ARHL) using prevalence matching with population-based data. METHODS: We chose 30, 25, 20, and 15 dB as gap ranges of cutoff values of the descending type of hearing loss, between an average of low (500 Hz, 1 kHz) and high (4 kHz, 6 kHz) frequencies. Interaural difference was defined as 10 or 15 dB. Hearing loss was defined over 25 dB. We compared the prevalence results of the cross-matching criteria. We used population-based data from the Korea National Health and Nutrition Examination Survey. We assumed that the prevalence of ARHL ranged from 25 to 35%, and this prevalence will increase gradually with age. RESULTS: Among the eight possible criteria, age ≥ 65 years, average of all frequencies > 25 dB at the each sides, gap between low- and high frequencies ≥ 20 dB, and interaural difference ≤ 10 dB were the most suitable criteria to suggest a quantitative definition of ARHL audiometrically. CONCLUSION: In the current study, we recommend the new, quantitative ARHL criteria. The suggested criteria for ARHL might be easily accessed by other researchers to demonstrate their own hypotheses.

Can Nutritional Intervention for Obesity and Comorbidities Slow Down Age-Related Hearing Impairment?

BACKGROUND: Age-related hearing impairment (ARHI), the most common sensory deficit in the elderly, is associated with enormous social and public health burdens. Emerging evidence has suggested that obesity and comorbidities might increase the risk of ARHI. However, no reviews have been published that address the role of nutritional interventions for obesity and comorbidities in the prevention of ARHI. METHODS: A PubMed database search was conducted to identify the relationship between obesity and ARHI. "Obesity", "metabolic syndrome", "adipose-derived hormone", "fatty acid", and "age-related hearing impairment" were included as keywords. RESULTS: A total of 89 articles was analyzed with 39 articles of relevance to ARHI. A high-fat diet may induce oxidative stress, mitochondrial damage, and apoptosis in the inner ear. Statins have been shown to delay the progression of ARHI by improving the lipid profile, reducing oxidative stress, and inhibiting endothelial inflammation. Aldosterone could exert protective effects against ARHI by upregulating the Na-K-2Cl co-transporter 1 in the cochlea. Omega-3 polyunsaturated fatty acids could preserve the cochlear microcirculation by reducing dyslipidemia and inhibiting inflammation. Alpha-lipoic acid and lecithin might delay the progression of ARHI by protecting cochlear mitochondrial DNA from damage due to oxidative stress. Tea and ginseng might protect against ARHI through their anti-obesity and anti-diabetic effects. CONCLUSIONS: Nutritional interventions for obesity and comorbidities, including a low-fat diet, supplementation with statins, aldosterone, omega-3 polyunsaturated fatty acids, alpha-lipoic acids, lecithin, tea, and ginseng, may protect against the development of ARHI.

Down-expression of P2RX2, KCNQ5, ERBB3 and SOCS3 through DNA hypermethylation in elderly women with presbycusis.

CONTEXT: Presbycusis, an age-related hearing impairment (ARHI), represents the most common sensory disability in adults. Today, the molecular mechanisms underlying presbycusis remain unclear. This is in particular due to the fact that ARHI is a multifactorial complex disorder resulting from several genomic factors interacting with lifelong cumulative effects of: disease, diet, and environment. OBJECTIVE: Identification of novel biomarkers for presbycusis. MATERIALS AND METHODS: We selectively ascertained 18 elderly unrelated women lacking environmental and metabolic risk factors. Subsequently, we screened for methylation map changes in blood samples of women with presbycusis as compared to controls, using reduced representation bisulfite sequencing. We focused on hypermethylated cytosine bases located in gene promoters and the first two exons. To elucidate the related gene expression changes, we performed transcriptomic study using gene expression microarray. RESULTS: Twenty-seven genes, known to be expressed in adult human cochlea, were found in the blood cells to be differentially hypermethylated with significant (p < 0.01) methylation differences (>30%) and down-expressed with fold change >1.2 (FDR <0.05). Functional annotation and qRT-PCR further identified P2RX2, KCNQ5, ERBB3 and SOCS3 to be associated with the progression of ARHI. DISCUSSION AND CONCLUSION: Down-expressed genes associated with DNA hypermethylation could be used as biomarkers for understanding complex pathogenic mechanisms underlying presbycusis.

White-matter microstructure and hearing acuity in older adults: a population-based cross-sectional DTI study.

To study the relation between the microstructure of white matter in the brain and hearing function in older adults we carried out a population-based, cross-sectional study. In 2562 participants of the Rotterdam Study, we conducted diffusion tensor imaging to determine the microstructure of the white-matter tracts. We performed pure-tone audiogram and digit-in-noise tests to quantify hearing acuity. Poorer white-matter microstructure, especially in the association tracts, was related to poorer hearing acuity. After differentiating the separate white-matter tracts in the left and right hemisphere, poorer white-matter microstructure in the right superior longitudinal fasciculus and the right uncinate fasciculus remained significantly associated with worse hearing. These associations did not significantly differ between middle-aged (51-69 years old) and older (70-100 years old) participants. Progressing age was thus not found to be an effect modifier. In a voxel-based analysis no voxels in the white matter were significantly associated with hearing impairment.

A nonsynonymous mutation in the WFS1 gene in a Finnish family with age-related hearing impairment.

Wolfram syndrome (WS) is caused by recessive mutations in the Wolfram syndrome 1 (WFS1) gene. Sensorineural hearing impairment (HI) is a frequent feature in WS and, furthermore, certain mutations in WFS1 cause nonsyndromic dominantly inherited low-frequency sensorineural HI. These two phenotypes are clinically distinct indicating that WFS1 is a reasonable candidate for genetic studies in patients with other phenotypes of HI. Here we have investigated, whether the variation in WFS1 has a pathogenic role in age-related hearing impairment (ARHI). WFS1 gene was investigated in a population sample of 518 Finnish adults born in 1938-1949 and representing variable hearing phenotypes. Identified variants were evaluated with respect to pathogenic potential. A rare mutation predicted to be pathogenic was found in a family with many members with impaired hearing. Twenty members were recruited to a segregation study and a detailed clinical examination. Heterozygous p.Tyr528His variant segregated completely with late-onset HI in which hearing deteriorated first at high frequencies and progressed to mid and low frequencies later in life. We report the first mutation in the WFS1 gene causing late-onset HI with audiogram configurations typical for ARHI. Monogenic forms of ARHI are rare and our results add WFS1 to the short list of such genes.

Corrigendum: Hearing Impairment Is Associated with Smaller Brain Volume in Aging.

[This corrects the article on p. 2 in vol. 9, PMID: 28163683.].

Association of genetic variations in the mitochondrial DNA control region with presbycusis.

BACKGROUND: The prominent role of mitochondria in the generation of reactive oxygen species, cell death, and energy production contributes to the importance of this organelle in the intracellular mechanism underlying the progression of the common sensory disorder of the elderly, presbycusis. Reduced mitochondrial DNA (mtDNA) gene expression and coding region variation have frequently been reported as being associated with the development of presbycusis. The mtDNA control region regulates gene expression and replication of the genome of this organelle. To comprehensively understand of the role of mitochondria in the progression of presbycusis, we compared variations in the mtDNA control region between subjects with presbycusis and controls. METHODS: A total of 58 presbycusis patients and 220 control subjects were enrolled in the study after examination by the otolaryngologist and audiology tests. Variations in the mtDNA control region were investigated by polymerase chain reaction and Sanger sequencing. RESULTS: A total of 113 sequence variants were observed in mtDNA, and variants were detected in 100% of patients, with 84% located in hypervariable regions. The frequencies of the variants, 16,223 C>T, 16,311 T>C, 16,249 T>C, and 15,954 A>C, were significantly different between presbycusis and control subjects. CONCLUSION: The statistically significant difference in the frequencies of four nucleotide variants in the mtDNA control region of presbycusis patients and controls is in agreement with previous experimental evidence and supports the role of mitochondria in the intracellular mechanism underlying presbycusis development. Moreover, these variants have potential as diagnostic markers for individuals at a high risk of developing presbycusis. The data also suggest the possible presence of changes in the mtDNA control region in presbycusis, which could alter regulatory factor binding sites and influence mtDNA gene expression and copy number.

The Association Between Age-Related Hearing Impairment and Metabolic Syndrome in Korean Women: 5-Year Follow-Up Observational Study.

BACKGROUND: Although several observational studies showed a relationship between various conditions of metabolic syndrome (MetS) and hearing threshold, there are no studies about longitudinal audiometric results related MetS. The aim of this study was to investigate the association between MetS and age-related hearing impairment (ARHI) through a large, average 5-year longitudinal follow-up, clinical comparative analysis. MATERIALS AND METHODS: We recruited 1381 women older than 50 years who were enrolled in 2007 and reevaluated in 2012. They had normal or symmetrical sensorineural hearing loss. For the evaluation of the independent impact of MetS on hearing, multivariate analysis was used. RESULTS: The average follow-up period was 5.0 ± 0.2 years. Subjects with MetS had higher hearing thresholds than subjects without MetS. The loss in high-frequency hearing (≥2000 Hz) progressed more rapidly in women with MetS over a 5-year period. CONCLUSION: Our analysis using longitudinal and large data revealed that MetS is associated with ARHI in women 50 years and older. High-frequency hearing loss tended to be greater in women with MetS than in those without MetS at the 5-year follow-up. Therefore, older women with MetS should be followed up closely for hearing evaluation.

Hearing Impairment Is Associated with Smaller Brain Volume in Aging.

Although recent studies show that age-related hearing impairment is associated with cerebral changes, data from a population perspective are still lacking. Therefore, we studied the relation between hearing impairment and brain volume in a large elderly cohort. From the population-based Rotterdam Study, 2,908 participants (mean age 65 years, 56% female) underwent a pure-tone audiogram to quantify hearing impairment. By performing MR imaging of the brain we quantified global and regional brain tissue volumes (total brain volume, gray matter volume, white matter (WM) volume, and lobe-specific volumes). We used multiple linear regression models, adjusting for age, sex, head size, time between hearing test and MR imaging, and relevant cognitive and cardiovascular covariates. Furthermore, we performed voxel-based morphometry to explore sub-regional differences. We found that a higher pure-tone threshold was associated with a smaller total brain volume [difference in standardized brain volume per decibel increase in hearing threshold in the age-sex adjusted model: -0.003 (95% confidence interval -0.004; -0.001)]. Specifically, WM volume was associated. Both associations were more pronounced in the lower frequencies. All associations were consistently present in all brain lobes in the lower frequencies and in most lobes in the higher frequencies, and were independent of cognitive function and cardiovascular risk factors. In voxel-based analyses we found associations of hearing impairment with smaller white volumes and some smaller and larger gray volumes, yet these were statistically non-significant. Our findings demonstrate that hearing impairment in elderly is related to smaller total brain volume, independent of cognition and cardiovascular risk factors. This mainly seems to be driven by smaller WM volume, throughout the brain.