Lois J. Matthews

Longitudinal study of pure-tone thresholds in older persons.

Objective: Pure-tone thresholds for conventional and extended high frequencies were analyzed for 188 older adult human subjects (91 females, 97 males). The objectives were to study longitudinal changes in thresholds as well as the effects of initial threshold levels, age, gender, and noise history on these longitudinal changes. Design: At the time of entry into the study, subjects’ ages ranged from 60 to 81 years, with a mean age of 68 years. Subjects had between 2 and 21 visits (mean = 9.81 visits) over a period of 3 to 11.5 years (mean = 6.40 years). Conventional pure-tone thresholds at 0.25 to 8 kHz were measured during most visits. Extended high-frequency (EHF) thresholds at 9 to 18 kHz were measured every 2 to 3 years. The slope of a linear regression was used to estimate the rate of change in pure-tone thresholds at 0.25 to 18 kHz for each ear. A questionnaire was used to identify those subjects with a positive noise history. Results: The average rate of change in thresholds was 0.7 dB per year at 0.25 kHz, increasing gradually to 1.2 dB per year at 8 kHz and 1.23 dB per year at 12 kHz. The rate of change for thresholds increased significantly with age, at 0.25 to 3, 10, and 11 kHz for females and at 6 kHz for males. After adjusting for age, females had a significantly slower rate of change at 1 kHz but a significantly faster rate of change at 6 to 12 kHz than males. For 0.25 and 1 kHz, subjects with more hearing loss at higher frequencies had a faster rate of change at these frequencies, whereas for 6 and 8 kHz, subjects with more hearing loss at mid and high frequencies had a slower rate of change at these frequencies. The rates of threshold change for subjects with a positive noise history were not statistically different from those with a negative noise history. Conclusions: On average, hearing threshold increased approximately 1 dB per year for subjects age 60 and over. Age, gender, and initial threshold levels can affect the rate of change in thresholds. Older female subjects (≥70 years) had faster rate of change at 0.25 to 3, 10, and 11 kHz than younger female subjects (60 to 69 years). Older male subjects had faster rate of change at 6 kHz than younger male subjects. Females had a slower rate of change at 1 kHz and a faster rate of change at 6 to 12 kHz than males. Subjects with higher initial thresholds at low and mid frequencies tended to have faster rate of threshold change at 0.25 to 2 kHz in the following years. Subjects with higher initial thresholds at mid and higher frequencies tended to have slower rate of change at 6 to 8 kHz in the following years. Noise history did not have a significant effect on the rate of threshold changes.

Classifying Human Audiometric Phenotypes of Age-Related Hearing Loss from Animal Models

Age-related hearing loss (presbyacusis) has a complex etiology. Results from animal models detailing the effects of specific cochlear injuries on audiometric profiles may be used to understand the mechanisms underlying hearing loss in older humans and predict cochlear pathologies associated with certain audiometric configurations (“audiometric phenotypes”). Patterns of hearing loss associated with cochlear pathology in animal models were used to define schematic boundaries of human audiograms. Pathologies included evidence for metabolic, sensory, and a mixed metabolic + sensory phenotype; an older normal phenotype without threshold elevation was also defined. Audiograms from a large sample of older adults were then searched by a human expert for “exemplars” (best examples) of these phenotypes, without knowledge of the human subject demographic information. Mean thresholds and slopes of higher frequency thresholds of the audiograms assigned to the four phenotypes were consistent with the predefined schematic boundaries and differed significantly from each other. Significant differences in age, gender, and noise exposure history provided external validity for the four phenotypes. Three supervised machine learning classifiers were then used to assess reliability of the exemplar training set to estimate the probability that newly obtained audiograms exhibited one of the four phenotypes. These procedures classified the exemplars with a high degree of accuracy; classifications of the remaining cases were consistent with the exemplars with respect to average thresholds and demographic information. These results suggest that animal models of age-related hearing loss can be used to predict human cochlear pathology by classifying audiograms into phenotypic classifications that reflect probable etiologies for hearing loss in older humans.

Longitudinal changes in speech recognition in older persons

Recognition of isolated monosyllabic words in quiet and recognition of key words in low- and high-context sentences in babble were measured in a large sample of older persons enrolled in a longitudinal study of age-related hearing loss. Repeated measures were obtained yearly or every 2 to 3 years. To control for concurrent changes in pure-tone thresholds and speech levels, speech-recognition scores were adjusted using an importance-weighted speech-audibility metric (AI). Linear-regression slope estimated the rate of change in adjusted speech-recognition scores. Recognition of words in quiet declined significantly faster with age than predicted by declines in speech audibility. As subjects aged, observed scores deviated increasingly from AI-predicted scores, but this effect did not accelerate with age. Rate of decline in word recognition was significantly faster for females than males and for females with high serum progesterone levels, whereas noise history had no effect. Rate of decline did not accelerate with age but increased with degree of hearing loss, suggesting that with more severe injury to the auditory system, impairments to auditory function other than reduced audibility resulted in faster declines in word recognition as subjects aged. Recognition of key words in low- and high-context sentences in babble did not decline significantly with age.

Gender‐Specific Effects of Drugs on Hearing Levels of Older Persons

ABSTRACT: As part of a study of human presbyacusis, a questionnaire on medicinal drug usage was given to 357 subjects (184 females, 173 males). Previous results from 211 subjects showed gender effects, that is, for males, none of the drugs had any measurable effects on hearing, whereas women taking calcium channel blockers (CCBs) had hearing levels 12 dB better than women not taking them; women taking β adrenergic medication had hearing levels 20 dB poorer, and women taking antihistamine/cold preparations had hearing levels 9 dB poorer. Results from the original 211 subjects were confirmed when the sample size was increased from 211 to 357 subjects only for the β adrenergic medications. Results for antihistamine/cold preparation medications showed small effects only for female subjects. Data from 13 additional female subjects who used CCBs showed hearing levels 10–14 dB poorer than predicted from the original data. Male data were consistent in both samples. The inconsistency for females could reflect sampling error. A more likely possibility is that since the original 10 subjects using CCBs had a mean age of 72 yr and the second sample of 13 had a mean age of 79.5 yr, poorer hearing levels might be anticipated because of the difference in chronological age and possibly duration of drug usage.

Age and Measurement Time-of-Day Effects on Speech Recognition in Noise

Objectives: The purpose of this study was to determine the effect of measurement time of day on speech recognition in noise and the extent to which time-of-day effects differ with age. Older adults tend to have more difficulty understanding speech in noise than younger adults, even when hearing is normal. Two possible contributors to this age difference in speech recognition may be measurement time of day and inhibition. Most younger adults are “evening-type,” showing peak circadian arousal in the evening, whereas most older adults are “morning-type,” with circadian arousal peaking in the morning. Tasks that require inhibition of irrelevant information have been shown to be affected by measurement time of day, with maximum performance attained at one’s peak time of day. The authors hypothesized that a change in inhibition will be associated with measurement time of day and therefore affect speech recognition in noise, with better performance in the morning for older adults and in the evening for younger adults. Design: Fifteen younger evening-type adults (20–28 years) and 15 older morning-type adults with normal hearing (66–78 years) listened to the Hearing in Noise Test (HINT) and the Quick Speech in Noise (QuickSIN) test in the morning and evening (peak and off-peak times). Time of day preference was assessed using the Morningness–Eveningness Questionnaire. Sentences and noise were presented binaurally through insert earphones. During morning and evening sessions, participants solved word-association problems within the visual-distraction task (VDT), which was used as an estimate of inhibition. After each session, participants rated perceived mental demand of the tasks using a revised version of the NASA Task Load Index. Results: Younger adults performed significantly better on the speech-in-noise tasks and rated themselves as requiring significantly less mental demand when tested at their peak (evening) than off-peak (morning) time of day. In contrast, time-of-day effects were not observed for the older adults on the speech recognition or rating tasks. Although older adults required significantly more advantageous signal-to-noise ratios than younger adults for equivalent speech-recognition performance, a significantly larger younger versus older age difference in speech recognition was observed in the evening than in the morning. Older adults performed significantly poorer than younger adults on the VDT, but performance was not affected by measurement time of day. VDT performance for misleading distracter items was significantly correlated with HINT and QuickSIN test performance at the peak measurement time of day. Conclusions: Although all participants had normal hearing, speech recognition in noise was significantly poorer for older than younger adults, with larger age-related differences in the evening (an off-peak time for older adults) than in the morning. The significant effect of measurement time of day suggests that this factor may impact the clinical assessment of speech recognition in noise for all individuals. It appears that inhibition, as estimated by a visual distraction task for misleading visual items, is a cognitive mechanism that is related to speech-recognition performance in noise, at least at a listener’s peak time of day.

Lipid and C-reactive Protein Levels as Risk Factors for Hearing Loss in Older Adults:

Objective To determine the role of cardiovascular disease (CVD) markers, lipids and C-reactive protein, in age-related hearing loss over time. Study Design Prospective cohort study. Setting Research laboratories at an academic medical center. Subjects and Methods In total, 837 older adults (mean age 67.5 years) were included. Primary dependent variables were pure-tone thresholds (pure-tone average [PTA]), including “narrow” PTA (0.5, 1, 2, 4 kHz), “broad” PTA (0.5, 1, 2, 3, 4, 6, 8 kHz), low-frequency PTA (0.25, 0.5, 1 kHz), and high-frequency PTA (2, 3, 4, 6, 8 kHz). Repeated-measures mixed regression modeling was used to assess the relationship between C-reactive protein (CRP) and lipid levels with PTAs over time. Results In a cross-sectional sample of 837 subjects, modest associations were found between triglycerides and all PTAs. Weak associations were observed between the ratio of total cholesterol and high-density lipoprotein and narrow PTA, broad PTA, and high-frequency PTA. However, when assessing changes in hearing and lipids over time in a longitudinal analysis, no significant associations between hearing and lipids remained. PTAs and CRP were not statistically associated when controlling for age and sex. Conclusion Associations between hearing and blood lipids have been the focus of scientific inquiry for more than 50 years. The current results suggest that the association is either spurious or too small to be of consequence in the assessment and treatment of hearing loss in older adults. Inquiry into other potential risk factors for age-related hearing loss and associations with CVD may prove more fruitful.

Self-Assessed Hearing Handicap in Older Adults With Poorer-Than-Predicted Speech Recognition in Noise

Purpose Even older adults with relatively mild hearing loss report hearing handicap, suggesting that hearing handicap is not completely explained by reduced speech audibility. Method We examined the extent to which self-assessed ratings of hearing handicap using the Hearing Handicap Inventory for the Elderly (HHIE; Ventry & Weinstein, 1982) were significantly associated with measures of speech recognition in noise that controlled for differences in speech audibility. Results One hundred sixty-two middle-aged and older adults had HHIE total scores that were significantly associated with audibility-adjusted measures of speech recognition for low-context but not high-context sentences. These findings were driven by HHIE items involving negative feelings related to communication difficulties that also captured variance in subjective ratings of effort and frustration that predicted speech recognition. The average pure-tone threshold accounted for some of the variance in the association between the HHIE and audibility-adjusted speech recognition, suggesting an effect of central and peripheral auditory system decline related to elevated thresholds. Conclusion The accumulation of difficult listening experiences appears to produce a self-assessment of hearing handicap resulting from (a) reduced audibility of stimuli, (b) declines in the central and peripheral auditory system function, and (c) additional individual variation in central nervous system function.

Joint modeling of multivariate hearing thresholds measured longitudinally at multiple frequencies

ABSTRACT Pure-tone thresholds are used to estimate hearing acuity and, when measured longitudinally, can characterize age-related changes in hearing. Measured at multiple-frequencies, multiple-irregular time points, for right and left ears, these longitudinal studies of age-related hearing loss produce data of inherent complexity due to: 1) multivariate outcomes at different frequencies; 2) longitudinal measurements taken at subject-specific time intervals; and 3) inter-ear correlations due to clustering and nesting. To address limitations in existing methods, we propose a multivariate generalized linear mixed model (mGLMM) and assess its performance. We demonstrate its application using a unique dataset from a cohort study of age-related hearing loss.

Transient-Evoked Otoacoustic Emissions Reflect Audiometric Patterns of Age-Related Hearing Loss:

Distinct forms of age-related hearing loss are hypothesized based on evidence from animal models of aging, which are identifiable in human audiograms. The Sensory phenotype results from damage (e.g., excessive noise or ototoxic drugs) to outer hair cells and sometimes inner hair cells, producing large threshold increases predominately at high frequencies. The Metabolic phenotype results from a decline in endocochlear potential that can reduce outer hair cell motility throughout the cochlea, producing gradually sloping thresholds from lower to higher frequencies. Finally, the combined Metabolic + Sensory phenotype results in low-frequency losses similar to the Metabolic phenotype and high-frequency losses similar to the Sensory phenotype. Because outer hair cell function appears to be affected differently in each phenotype, this study used audiograms from 618 adults aged 50 to 93 years (n = 1,208 ears) to classify phenotypes and characterize differences in transient-evoked otoacoustic emission (TEOAE) data. Significant phenotype differences were observed in frequency-band TEOAEs and configuration (intercept and slope), including large and broadly distributed TEOAE reductions for Metabolic and Metabolic + Sensory ears and more focused high-frequency TEOAE reductions for Sensory ears. These findings are consistent with metabolic declines that reduce cochlear amplification across a broad range of frequencies and more basally situated, high-frequency declines in sensory hearing loss. The results provide further validation for the classification of age-related hearing loss phenotypes based on audiograms and show human TEOAE declines that are highly consistent with animal models.

Whole exome sequencing in adult-onset hearing loss reveals a high load of predicted pathogenic variants in known deafness-associated genes and identifies new candidate genes

BackgroundDeafness is a highly heterogenous disorder with over 100 genes known to underlie human non-syndromic hearing impairment. However, many more remain undiscovered, particularly those involved in the most common form of deafness: adult-onset progressive hearing loss. Despite several genome-wide association studies of adult hearing status, it remains unclear whether the genetic architecture of this common sensory loss consists of multiple rare variants each with large effect size or many common susceptibility variants each with small to medium effects. As next generation sequencing is now being utilised in clinical diagnosis, our aim was to explore the viability of diagnosing the genetic cause of hearing loss using whole exome sequencing in individual subjects as in a clinical setting.MethodsWe performed exome sequencing of thirty patients selected for distinct phenotypic sub-types from well-characterised cohorts of 1479 people with adult-onset hearing loss.ResultsEvery individual carried predicted pathogenic variants in at least ten deafness-associated genes; similar findings were obtained from an analysis of the 1000 Genomes Project data unselected for hearing status. We have identified putative causal variants in known deafness genes and several novel candidate genes, including NEDD4 and NEFH that were mutated in multiple individuals.ConclusionsThe high frequency of predicted-pathogenic variants detected in known deafness-associated genes was unexpected and has significant implications for current diagnostic sequencing in deafness. Our findings suggest that in a clinic setting, efforts should be made to a) confirm key sequence results by Sanger sequencing, b) assess segregations of variants and phenotypes within the family if at all possible, and c) use caution in applying current pathogenicity prediction algorithms for diagnostic purposes. We conclude that there may be a high number of pathogenic variants affecting hearing in the ageing population, including many in known deafness-associated genes. Our findings of frequent predicted-pathogenic variants in both our hearing-impaired sample and in the larger 1000 Genomes Project sample unselected for auditory function suggests that the reference population for interpreting variants for this very common disorder should be a population of people with good hearing for their age rather than an unselected population.