Darker blue and purple areas are regions associated with higher annual rate of gray matter decline per 10-dB difference in the better-ear pure tone average, whereas deeper red denotes regions associated with slower annual rates of decline in gray matter per 10-dB hearing level increase in pure tone average. Color bars denote regression coefficient t values (regression coefficient/SE). Regions shown in this figure are hippocampus, entorhinal cortex, parahippocampal gyrus, superior, middle, and inferior temporal gyri, temporal pole, planum polare, planum temporale, and transverse temporal gyrus.
eFigure 1. Selection of study participants from the Baltimore Longitudinal Study of Aging (BLSA) Neuroimaging Substudy
eFigure 2. Template and ROI selection from MUSE labeling.
eFigure 3. Template of lobar white matter regions using MUSE algorithm.
eFigure 4. Scatterplot of pure tone average in the right vs left ear in the Baltimore Longitudinal Study of Aging (N = 192)
Customize your JAMA Network experience by selecting one or more topics from the list below.
Armstrong NM, An Y, Doshi J, et al. Association of Midlife Hearing Impairment With Late-Life Temporal Lobe Volume Loss. JAMA Otolaryngol Head Neck Surg. 2019;145(9):794–802. doi:10.1001/jamaoto.2019.1610
Is midlife hearing impairment associated with late-life temporal lobe volume loss, and does laterality of hearing impairment matter?
In this cohort study of 194 community-dwelling older adults, midlife hearing impairment in the better ear was associated with volumetric declines in the right hippocampus and left entorhinal cortex. Midlife hearing impairment in the right ear was associated with steeper volumetric declines in the right temporal gray matter, right hippocampus, and left entorhinal cortex.
The findings suggest that midlife hearing impairment is associated with increased risk of volumetric decline in temporal lobe structures affected by Alzheimer disease; associations of hearing and temporal lobe volumes may differ by laterality of hearing impairment, suggesting a role of right ear dominance on regional volume loss.
Hearing impairment (HI) in midlife (45-65 years of age) may be associated with longitudinal neurodegeneration of temporal lobe structures, a biomarker of early Alzheimer disease.
To evaluate the association of midlife HI with brain volume trajectories in later life (≥65 years of age).
Design, Setting, and Participants
This prospective cohort study used data from the Baltimore Longitudinal Study of Aging to evaluate hearing from November 5, 1990, to October 3, 1994, and late-life volume change from July 10, 2008, to January 29, 2015, using magnetic resonance imaging (MRI) (mean follow-up time, 19.3 years). Data analysis was performed from September 22, 2017, to August 27, 2018. A total of 194 community-dwelling older adults who had midlife measures of peripheral hearing at a mean age of 54.5 years and late-life volume change of up to 6 years between the first and most recent MRI assessment were studied. Excluded were those with baseline cognitive impairment, stroke, head injuries, Parkinson disease, and bipolar disorder.
Hearing as measured with pure tone audiometry in each ear from November 5, 1990, to October 3, 1994, and late-life temporal lobe volume change measured by MRI.
Main Outcomes and Measures
Linear mixed-effects models with random intercepts were used to examine the association of midlife hearing (pure tone average of 0.5-4 kHz tones in the better ear and each ear separately) with longitudinal late-life MRI-based measures of temporal lobe structures (hippocampus, entorhinal cortex, parahippocampal gyrus, and superior, middle, and inferior temporal gyri) in the left and right hemispheres, in addition to global and lobar regions, adjusting for baseline demographic characteristics (age, sex, subsequent cognitive impairment status, and educational level) and intracranial volume.
A total of 194 patients (mean [SD] age at hearing assessment, 54.5 [10.0] years; 106 [54.6%] female; 169 [87.1%] white) participated in the study. After Bonferroni correction, poorer midlife hearing in the better ear was associated with steeper late-life volumetric declines in the right temporal gray matter (β = −0.113; 95% CI, −0.182 to −0.044), right hippocampus (β = −0.008; 95% CI, −0.012 to −0.004), and left entorhinal cortex (β = −0.009; 95% CI, −0.015 to −0.003). Poorer midlife hearing in the right ear was associated with steeper late-life volumetric declines in the right temporal gray matter (β = −0.136; 95% CI, −0.197 to −0.075), right hippocampus (β = −0.008; 95% CI, −0.012 to −0.004), and left entorhinal cortex (β = −0.009; 95% CI, −0.015 to −0.003), whereas there were no associations between poorer midlife hearing in the left ear with late-life volume loss.
Conclusions and Relevance
The findings suggest that midlife HI is a risk factor for temporal lobe volume loss. Poorer midlife hearing, particularly in the right ear, was associated with declines in hippocampus and entorhinal cortex.
Alzheimer disease (AD), a neurodegenerative process that is a leading cause of dementia and death in the United States, is associated with changes in brain volumes.1 Approximately 5.3 million Americans 65 years and older had an AD diagnosis in 2017, and AD prevalence is expected to continue to increase as the population of older adults grows.2 Brain changes (ie, volume loss) in the AD preclinical phase may begin as early as 20 years before symptoms appear.3-6 Longitudinal MRI-based measures, as biomarkers of neurodegeneration and AD pathologic findings, can be used to estimate trajectories of global and regional brain volume loss.7
Midlife and late-life hearing impairment (HI), a prevalent condition that affects more than half of older adults in the United States,8 is a risk factor for dementia.9 Livingston et al9 suggest that a 9% reduction in dementia cases would occur if HI were prevented or treated. Age-related HI results from progressive damage to the cochlea associated with many factors (eg, aging, noise, and cardiovascular risk factors) that led to poorer encoding of sound by the cochlea. Hypothesized mechanisms underlying the association of HI with AD onset include cognitive load from reallocation of brain resources for auditory processing,10 change in brain structure and function,11-13 and decreased social engagement.14,15
By examining the association of hearing with longitudinal MRI-based markers that are proxies for neurodegeneration, we can examine one potential mechanistic pathway that links HI with cognitive decline and dementia. Previous research16 has demonstrated changes in cortical reorganization and brain morphometry associated with HI. Because auditory signals are processed by the primary auditory cortex located in the superior and transverse temporal gyri,17 HI could plausibly affect these and surrounding brain regions (ie, hippocampus, entorhinal cortex, and parahippocampal gyrus).18-20 However, findings from several studies16,18,21-24 are mixed. Some studies reported that HI in older adults is associated with lower gray matter (GM) volume in the primary auditory cortex16,21,22 and accelerated rates of GM volume decline in the right temporal lobe,18 whereas 2 other cross-sectional studies23,24 reported no association between HI and GM. All studies16,18,21-24 consisted of samples of older adults and did not evaluate whether midlife HI was associated with longitudinal change in GM volumes.
To evaluate the association of midlife HI with late-life brain volume trajectories, we examined Baltimore Longitudinal Study of Aging (BLSA)25 participants who had available hearing and neuroimaging data. We hypothesized that greater HI is associated with subsequent tissue loss in temporal lobe structures, with stronger associations for the right than left hemisphere, based on our prior findings.18
To explore these associations further, we investigated how measures of hearing in the right and left ears may differ in their associations with brain volume changes. There could be lateralized differences in how hearing affects changes in brain structure, which could be attributed to the right ear advantage.26 The right ear advantage postulates that contralateral pathways are strongest for speech and language processing, which occurs predominantly in the left hemisphere. Tadros et al27 found that older adults with normal hearing had right-ear dominance, whereas older adults with HI had diminished right-ear dominance. We hypothesized that the association of HI with temporal volume loss may vary by ear, with stronger associations for the right ear.
This cohort study included community-dwelling volunteers who were followed up in the BLSA neuroimaging substudy28 with audiometric data collected from November 5, 1990, to October 3, 1994, and data from at least 1 magnetic resonance imaging (MRI) assessment collected from July 10, 2008, to January 29, 2015 (N = 194 with 391 observations). eFigure 1 in the Supplement shows the sample selection. Enrollment procedures are described elsewhere.29 The institutional review boards governing the National Institute on Aging Intramural Research Program approved the research protocol for this study, and written informed consent was obtained at each visit from all participants. All data were deidentified at the analysis stage.
Exclusion criteria for our analyses were based on significant health conditions that could affect brain structure or function (ie, stroke, closed head injury, cranial or brain surgery, malignant cancer, gliomas, intracranial cysts with brain tissue displacement, seizure, and bipolar disorders). Although the hearing data overlapped with our prior report (47 participants were included in both analyses),18 MRI visits for participants aged 60 to 79 years were performed biennially, whereas MRI visits for participants 80 years or older were performed annually. Baseline was defined as the first MRI. We excluded 12 participants with cognitive impairment at first MRI.
Pure tone audiometric testing, a criterion standard measure of the sensitivity of the peripheral auditory system,30 was performed using a semiautomated testing device (audiometer model 320; Virtual Equipment Co) in a sound-attenuating booth. A speech-frequency pure tone average (PTA) of air-conduction thresholds at 0.5, 1, 2, and 4 kHz was calculated for each ear. All thresholds were measured in decibels hearing level (HL). Most participants underwent 1 audiometric test between 1990 and 1994, but some participants had 2 audiometric tests during this period. The second test was used in this instance because hearing may worsen over time.31 We multiplied PTA by 10 to examine the difference by 10 dB HL in PTA.
From 2008 to 2015, T1-weighted magnetization-prepared rapid gradient echo scans were acquired on a 3-T Philips Achieva (repetition time, 6.8 milliseconds; echo time, 3.2 milliseconds; flip angle, 8°; image matrix, 256 × 256; 170 sections; pixel size, 1 × 1 mm; section thickness, 1.2 mm).
Using a multi-atlas label fusion approach, we applied a new automated labeling method that is specifically designed to achieve a consistent parcellation of brain anatomy in longitudinal MRI studies with scanner and imaging protocol differences on T1-weighted sequences in the BLSA MRI data. The MUSE (Multi-atlas Region Segmentation Utilizing Ensembles) anatomic labeling approach32 generates an ensemble of labeled atlases in target image space by combining different atlases, warping algorithms, and regularization parameters and uses a consensus labeling approach to fuse these labels into a final segmentation. The MUSE workflow for anatomical labeling has been extensively validated on the BLSA MRI data set.33 eFigure 2 in the Supplement shows selected regions of interest (ROIs) associated with the MUSE workflow for anatomical labeling, and eFigure 3 in the Supplement shows the white matter (WM) regions defined by the MUSE workflow.
We examined global and lobar GM and WM ROIs in addition to temporal lobe subregions (superior, middle, and inferior temporal gyri, hippocampus, parahippocampal gyrus, and entorhinal cortex), areas known to be related to volume loss associated with HI.18 In addition, we examined other regions and structures within the temporal lobe to determine whether HI affected other areas of the temporal lobe. The primary auditory cortex is located on the superior temporal gyrus with indirect projections from the hippocampus and is surrounded by brain structures implicated in AD.19,20 Reduced auditory input is associated with hippocampal degeneration and impaired memory function.34 Additional ROIs were fusiform gyrus, temporal pole, and supratemporal GM, consisting of the planum polare, planum temporale, and transverse temporal gyrus.
Adjustment variables included demographic characteristics (age at first MRI, sex, cognitive status, and educational level) and vascular burden. We adjusted by these characteristics because demographic characteristics and vascular burden are associated with cognitive decline and AD.1 Cognitive status was defined as developing subsequent cognitive impairment after baseline or remaining cognitively normal throughout the study period. The procedures for determination of subsequent cognitive impairment, by diagnosis of mild cognitive impairment or dementia and/or AD, have been detailed previously.28 Cognitive impairment was determined through consensus case conference, using the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria35 for dementia and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for AD.36 Mild cognitive impairment was determined by Petersen criteria.37 We included cognitive status because trajectories of volume loss are steeper in subsequently impaired adults compared with cognitively normal adults.38 The number of cardiovascular risk factors (ie, current smoking status, hypertension, diabetes, obesity, and elevated total cholesterol level) was summed to evaluate cumulative vascular burden.39 Few, if any, participants had 2 or more cardiovascular risk factors; thus, vascular burden was categorized as present vs absent.
We characterized the sample using means of continuous variables and percentages of categorical variables. Linear mixed-effect models with random intercepts and unstructured variance-covariance structure were used to evaluate the associations of midlife hearing with trajectories of each MRI-defined brain volume. All models included a time-invariant midlife hearing measure, baseline intracranial volume, sex, cognitive status, baseline age, and educational level. Annual rates of volumetric change are defined by the estimates for the 2-sided time effect. Two-way interactions of hearing, sex, and cognitive status with time since first MRI assessment were included in the models. We tested these 2-way interactions to allow for the annual rates of change to accelerate or decelerate as a function of the covariates of interest. We also did not include vascular burden and 2-way interactions of vascular burden with time in our final models because the addition of these variables did not affect the estimated association of PTA with baseline and annual rates of volume change in brain volumes and model fit did not improve with the addition of these variables. We also examined models with a 3-way interaction among PTA, sex, and time since first MRI assessment. Observations after cognitive impairment were excluded. Results are reported as significant for regional brain volume associations at P = .002 after using a highly conservative Bonferroni correction for multiple comparisons because we examined 31 ROIs in the main analysis.
In exploratory analyses, we evaluated each ear separately in relation to rates of change in brain volumes to determine whether there was a right ear advantage, which postulates that contralateral pathways are strongest for speech and language processing, occurring predominantly in the left hemisphere.26 We used linear mixed models to examine PTA recorded for right and left ears to determine whether there was an ipsilateral or contralateral association with brain volumetric change. We excluded 2 observations from this analysis because these 2 observations from PTA measured in the left ear had a greater than 90 dB HL. Significance testing for ROI analysis was 2-sided with a type I error of 0.05, and results are reported as significant at P = .001 after Bonferroni correction because we examined 45 ROIs in these exploratory analyses. All results are reported in tables to guide future research because many comparisons were significant at P < .05. The statistical software used was R, version 3.4.0 (R Foundation)40 and Stata SE, version 15.0 (StataCorp).41 Data analysis was performed from September 22, 2017, to August 27, 2017.
A total of 194 patients (mean [SD] age at hearing assessment, 54.5 [10.0] years; 106 [54.6%] female; 169 [87.1%] white) participated in the study. Table 1 gives the sample characteristics. The mean (SD) educational level was 17.1 (2.3) years, and the mean (SD) time from hearing assessment was 19.5 (1.9) years. The mean (SD) PTA was 13.7 (11.6) dB HL. A total of 26 participants (13.4%) had mild HI and 6 (3.1%) had moderate to severe HI. The mean (SD) follow-up was 1.4 (1.7) years in the overall sample when those with a single MRI assessment were included. Among the 103 participants with 2 or more serial MRI assessments, the mean (SD) follow-up was 3.2 (1.3) years. A total of 121 participants (62.4%) had 1 or more cardiovascular risk factors. The most common ones were elevated cholesterol level (51 [26.4%]), obesity (50 [25.8%]), and hypertension (41 [21.1%]).
The association of poorer midlife hearing with baseline and changes in volumes of global, lobar, ventricles, and selected brain regions (hippocampus, entorhinal cortex, parahippocampal gyrus, and superior, middle, inferior temporal gyri) from 2008 to 2015 are given in Table 2. At baseline, a 10-dB HL difference in PTA among participants was associated with lower volumes in the right superior temporal gyrus (β = −0.123; 95% CI, −0.229 to −0.017). Many associations were found between HI and greater ventricular enlargement and annual volume loss in total brain, lobar GM and WM regions, right middle and inferior temporal gyri, and left hippocampus (Table 2). After Bonferroni correction, poorer midlife hearing was associated with steeper volumetric declines in the right temporal GM (β = −0.113; 95% CI, −0.182 to −0.044), right hippocampus (β = −0.008; 95% CI, −0.012 to −0.004), and left entorhinal cortex (β = −0.009; 95% CI, −0.015 to −0.003) (Table 2). The Figure shows the volumetric decline in the selected ROIs in the temporal lobe per 10-dB HL difference in PTA. No significant 3-way interactions were found among sex, poorer midlife hearing, and time.
We further investigated whether there were lateralized differences in the associations of poorer midlife hearing of the right and left ears with rates of brain volumetric change (Table 3). We examined the correlation and scatterplot between PTA from the right vs left ear. The Pearson correlation between the PTA from both ears was 0.717 (95% CI, 0.583-0.785) (eFigure 4 in the Supplement). At baseline, poorer midlife hearing in the right ear was associated with decreased baseline volume in the right superior temporal gyrus (β = −0.107; 95% CI, −0.195 to −0.019) (Table 3). Poorer midlife hearing in the right ear was longitudinally associated with greater ventricular enlargement and steeper volumetric declines in lobar GM, WM, and temporal lobar structures (bilateral hippocampi, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, inferior temporal gyrus, temporal pole, right middle temporal gyrus, and left amygdala and superior temporal gyrus) (Table 3). After Bonferroni correction, poorer midlife hearing in the right ear was associated with steeper volumetric declines in the right temporal GM (β = −0.136; 95% CI, −0.197 to −0.075), right hippocampus (β = −0.008; 95% CI, −0.012 to −0.004), right temporal pole (β = −0.028; 95% CI, −0.042 to −0.014), and left entorhinal cortex (β = −0.009; 95% CI, −0.015 to −0.003) (Table 2).
In contrast, poorer midlife hearing in the left ear was associated with greater baseline volumes in the left supratemporal GM (β = 0.074; 95% CI, 0.009-0.139), particularly in the transverse temporal gyrus (β = 0.034; 95% CI, 0.001-0.067). It was longitudinally associated with volume loss in temporal GM and hippocampus bilaterally, left occipital GM, left entorhinal cortex, right fusiform gyrus, right inferior temporal gyrus, and right temporal pole (Table 3). No associations of poorer midlife hearing in the left ear with baseline and annual rates of change in brain volume were found after Bonferroni correction (Table 3).
Greater midlife HI was associated with late-life volumetric declines in temporal structures affected by AD pathologic findings. Poorer midlife hearing was associated with steeper volumetric declines in the right temporal GM, right hippocampus, and left entorhinal cortex during a mean follow-up interval between hearing assessment and MRI of 19.5 years. When considering poorer midlife hearing by ear, we found that poorer midlife hearing in the right ear was associated with steeper volumetric declines in the right temporal GM, right hippocampus, right temporal pole, and left entorhinal cortex, whereas there were no associations of poorer midlife hearing in the left ear with rate of volume change after Bonferroni correction.
Our study results differ from those of a prior BLSA study by Lin et al18 in the specific regions associated with HI, but that study investigated whether late-life (rather than midlife) HI was associated with rates of change in brain tissue volumes. The authors reported that individuals with late-life HI had accelerated rates of tissue loss in right superior, middle, and inferior temporal gyri, regions implicated in spoken language processing, semantic memory, and sensory integration,12,42 as well as whole brain atrophy, a proxy for neurodegeneration, for a mean follow-up period of 6 years. We found similar results when applying less stringent criteria for statistical significance, suggesting that midlife HI is associated with accelerated rate of tissue loss in these areas.
Results in the current study showed that poorer midlife hearing was associated with GM volumetric declines in the right hippocampus and left entorhinal cortex, structures that are affected early in the AD course.1 These findings suggest that HI could affect temporal lobe structures, producing cascading effects on neighboring structures implicated in cognitive impairment. Age-related HI can result in poorer encoding of sound by the cochlea.43,44 As a consequence, poor auditory signals and reduced stimulation from the impaired cochlea may produce changes in cortical organization and brain morphometry.16 Cochlear impairments have been shown to be associated with changes in central neuronal structures in animal models.45 Effects of impoverished and degraded auditory signaling from HI could potentially result in GM atrophy of regions associated with auditory and cognitive processing. On the basis of these findings, changes in brain structure, especially temporal lobe structures affected by early AD pathologic findings, may partially mediate the association of HI with dementia onset observed in epidemiologic studies.9,46-48 Even if the reported effects are secondary consequences of HI, these could be associated with subsequent dementia by lowering the threshold of volume loss associated with clinical symptoms.
We compared the rates of change in brain volume with poorer midlife hearing in the right vs left ears as an exploratory aim of this study. The rationale for this exploratory analysis was that there are known hemispheric differences in auditory processing, leading to a right ear advantage.26 We observed that greater HI in the right ear was associated with steeper volumetric declines in more regions located within the temporal lobe compared with HI in the left ear. This finding suggests that there may be strong lateralized differences in how hearing may affect the brain, which could be attributed to the right ear advantage.26 Further research is needed to confirm these results in larger cohorts and to explore the mechanistic basis of these possible associations.
There are several limitations to this study. First, the results of this study are not generalizable to all community-dwelling older adults because the volunteers tended to be more highly educated and have a high socioeconomic status. Although this is a limitation, it may also strengthen the internal validity of our findings, given the relative homogeneity of the study cohort in observed and unobserved characteristics. Second, we examined late-life trajectories of volumetric change, which decreased our sample size and number of observations, reducing power to detect associations. However, the lengthy interval between collection of data on HI and brain measures allowed us to investigate associations of midlife HI with brain changes a mean of approximately 19 years after midlife hearing assessment. A third limitation could be from residual confounding. An unmeasured factor (ie, inflammation, microvascular disease) could potentially underlie cochlear and brain aging and not be accounted for in our analytic models. Other factors not measured (ie, social disengagement and depression) could interact with HI to accelerate neurodegeneration because social disengagement15 and depression49 are known risk factors of cognitive decline and dementia. Only 5 participants (2.6%) had clinically relevant depressive symptoms at baseline; thus, we did not examine the association of depressive symptoms and HI with volumetric change. Few participants used hearing aids in this sample18; thus, we were unable to examine whether hearing aid use affected the associations of HI with neurodegeneration. Moreover, 83% of our sample had normal hearing in midlife. Associations seen in this study could be even greater in samples with greater frequency and severity of HI. Fourth, information on tinnitus, a condition that occurs in approximately 50% of those with clinically defined HI, was unavailable, which may affect associations between HI and GM volumes.
We observed that midlife HI was associated with greater late-life atrophy over time in certain temporal lobe structures implicated in auditory processing and AD for a mean follow-up period of 19.5 years in 194 men and women. These findings support the hypothesis that midlife HI may be a risk factor for dementia in older adults via changes in brain structures. The variety of mechanisms that may underlie the association between HI and subsequent late-life brain volume loss merit further investigation.
Accepted for Publication: May 6, 2019.
Corresponding Author: Susan M. Resnick, PhD, Intramural Research Program, National Institute on Aging, 251 Bayview Blvd, Baltimore, MD 21224-6825 (firstname.lastname@example.org).
Published Online: July 3, 2019. doi:10.1001/jamaoto.2019.1610
Author Contributions: Drs Lin and Resnick are joint senior authors. Drs Resnick and Armstrong had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Armstrong, Lin, Resnick.
Acquisition, analysis, or interpretation of data: Armstrong, An, Doshi, Erus, Ferrucci, Davatzikos, Deal, Resnick.
Drafting of the manuscript: Armstrong, An, Davatzikos, Lin.
Critical revision of the manuscript for important intellectual content: Armstrong, Doshi, Erus, Ferrucci, Deal, Lin, Resnick.
Statistical analysis: Armstrong, An, Doshi, Erus, Davatzikos.
Obtained funding: Resnick.
Supervision: Erus, Lin, Resnick.
Conflict of Interest Disclosures: Dr Davatzikos reported receiving grants from the Baltimore Longitudinal Study of Aging during the conduct of the study. Dr Lin reported receiving personal fees from Boehringer Ingelheim, Cochlear Ltd, Caption Call, and Triton Hearing outside the submitted work and being the director of the Cochlear Center for Hearing and Public Health at the Johns Hopkins Bloomberg School of Public Health, which is funded in part by a gift from Cochlear Ltd to Johns Hopkins University. No other disclosures were reported.
Funding/Support: This research was supported fully by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Dr Davatzikos was supported in part by grant RF1 AG054409 from the National Institutes of Health.
Role of the Funder/Sponsor: The authors of this manuscript include employees of the Intramural Research Program of the National Institute on Aging, who participated in all aspects of the project. Other than that, the sponsor did not have a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the participants and staff of the Baltimore Longitudinal Study of Aging, the neuroimaging staff of the Laboratory of Behavioral Neuroscience, and the staff of the Johns Hopkins and National Institute on Aging magnetic resonance imaging facilities.