This cohort study compares the risk of incident all-cause dementia among people with hearing loss who use vs do not use hearing aids.

Importance:Hearing loss is an impactful chronic condition among aging adults; however, little is known about the incidence and natural history of hearing loss. Objective:To examine the 25-year cumulative incidence and progression of hearing loss and determine associated factors. Design, Setting, and Participants:This study was conducted in the Framingham Offspring Study cohort in Framingham, Massachusetts. Participants were included if they had data from examinations 6 (baseline: 1995 to 1998) and 10 (follow-up: 2019 to 2022). Incidence analyses included 436 participants at risk of hearing loss, which was defined as no baseline hearing loss. Analyses focused on progression of hearing loss included the 511 participants with audiometric data from both examinations. Data were analyzed from November 26, 2024, to August 15, 2025. Exposures:Possible risk factors included self-reported age, sex, education, noise exposure history, smoking and heavy drinking, and measured hypertension, stroke risk (Framingham Stroke Risk Profile [FSRP]), low-density lipoprotein, high-density lipoprotein, and total cholesterol, fasting blood glucose, systolic and diastolic blood pressure, and waist circumference. Main Outcomes and Measures:Hearing was defined by the worse-ear pure-tone average (PTA) of thresholds at frequencies 0.5, 1.0, 2.0, and 4.0 kHz. Hearing loss was defined as PTA more than 25 dB HL, and progression as annualized increase in PTA. We used age- and sex-adjusted logistic and linear regression models to determine factors associated with incidence and progression of hearing loss; models were stratified by sex or baseline age (ie, ≤50 or >50 years) when interactions were present. Results:The 511 participants had a mean (SD) age of 52.2 (7.2; range, 34.7-74.4) years and 212 were male (41.5%). The 25-year cumulative incidence (among 436 at-risk participants) was 56.2% (246 participants) and the mean (SD) hearing loss progression was 15.1 (11.6) dB. Factors associated with incident hearing loss included older age, lower education, and high noise exposure, and, among participants aged more than 50 years, hypertension and higher FSRP. Factors associated with hearing loss progression included older age, female sex, lower education, and among participants aged more than 50 years, hypertension and higher diastolic blood pressure. Conclusions and Relevance:In this cohort study, the 25-year incidence and progression of hearing loss was examined. Findings corroborate hearing loss as an important public health concern that may be at least partially preventable.

Sensorineural hearing loss (SNHL) is a hallmark symptom in patients with neurofibromatosis type 2-associated schwannomatosis (NF2-SWN), a genetic condition caused by mutations in the Neurofibromin II gene that encodes the tumor suppressor protein Moesin-Ezrin-Radixin-Like Protein (Merlin; also known as schwannomin). These mutations lead to the development of various tumors, including schwannomas, ependymomas and meningiomas along the vestibular nerve and the cerebellopontine angle. Original theories attributed SNHL in NF2-SWN to the mechanical compression of the vestibulocochlear nerve from the tumor itself, in addition to secretion of toxic tumor byproducts. However, the observation that SNHL can progress independently of tumor size and growth dynamics challenges this view and reveals a critical gap in our understanding of its underlying etiology. To better define cochlear changes associated with hearing loss in NF2-SWN, immunohistochemical cell type markers were used on archival postmortem temporal bone samples from both NF2-SWN patients and healthy controls and quantified the number and cellular density of neural (TUJ1), glial (SOX10), and immune cells (IBA1) within apical, middle, and basal turns of the cochlea. Our findings demonstrated a significant loss of spiral ganglion neurons, a slight increase of Schwann cells, and marked activation of cochlear macrophages in NF2-SWN cases. These findings indicate the contribution of cochlear macrophage-mediated inflammation and Schwann cell dysregulation in the pathophysiology of SNHL in NF2-SWN.

Surgical intervention for vestibular schwannomas (VS) is typically considered when a large or growing tumor is diagnosed. Several surgical approaches are used to access the internal acoustic canal and cerebellopontine angle for resections of VS, each with unique advantages and disadvantages. The choice of surgical approach is guided by tumor size, location, and preoperative hearing status. Tumor control, facial nerve (FN) function protection, and hearing preservation are the main goals in treating VS. Excellent tumor control outcomes with stereotactic radiation in recent decades, and the recognition that aggressive surgical resection places the FN at risk have led to a shift in treatment philosophy for VS. Recent broadening of approved indications for cochlear implantation and advances in auditory brainstem implant technology have also provided new options in hearing rehabilitation for patients with VS.

Objective:The primary objective of this study is to review the evidence for aspirin use to prevent the growth of vestibular schwannomas (VS) and to propose a prospective trial to determine the progression-free survival of VS patients after up to 42 months of treatment with aspirin. Secondary study objectives are to determine the effect of aspirin on VS growth, hearing function, serum biomarker levels, and the quality of life, as well as to determine the tolerability of aspirin treatment and whether serum biomarker and salicylate levels predict the response to aspirin. Study Design:Literature review. Setting:Six academic and private medical centers. Methods:Review of recent English literature regarding prophylactic aspirin use for VS. Results:The retrospective reviews on the utility of aspirin to prevent VS growth are inconclusive. Eighty-four patients have been enrolled in a prospective double-blinded, placebo-controlled trial thus far to determine the effect of aspirin on VS. Conclusions:Completion of a robust study design is necessary. The current aspirin dose has been well tolerated, with minimal adverse events to date. Level of Evidence:Review of retrospective studies: Level 4; Proposed randomized, placebo-controlled, double-blinded clinical trial: Level 2.

Rapidly progressing bilateral hearing loss may indicate intracranial metastatic malignancy. MRI and CT imaging can provide useful information on symptom etiology, and as with this coronal CT image of the sinuses and anterior skull base revealing a right ethmoid/cribriform mass (arrow), accessible areas for timely diagnostic biopsy may be identified.

Vertebrate embryogenesis requires the precisely timed specification of 3 germ cell layers- ectoderm, mesoderm, and endoderm- which give rise to tissues and organs in the developing organism. The tumor suppressor gene NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (Nf2) is expressed in all 3 germ layers during mouse development and its homozygous deletion causes embryonic lethality. People with heterozygous NF2 mutations typically develop Schwann cell tumors, especially vestibular schwannoma, but the specific role of NF2 in human embryonic development is unclear. Here, human induced pluripotent stem cells (hiPSCs) are used to demonstrate that NF2 is essential for endoderm specification and formation in humans. Although endoderm differentiation is not impaired in hiPSCs with heterozygous NF2 mutation, NF2 knockout (NF2-/-) abolished the capacity to form endoderm in vitro, confirmed by loss of expression of endoderm-related genes and proteins, or teratomas in vivo. This defect is mediated by the nuclear translocation of yes-associated protein 1 (YAP1), a transcription co-activator regulating lineage fate via the Hippo pathway and subsequent YAP1-mediated shutdown of Activin/Nodal signaling. Endoderm formation can be rescued via YAP1 knockdown or forced re-expression of NF2 in NF2-/- cells. Taken together, the essential role of NF2 during endoderm specification in human embryogenesis as a regulator of YAP1 is reported.

OBJECTIVES:To determine if the chronic use of bevacizumab, prior to withholding for elective surgery in the preoperative period, increases the risk of hemorrhage during vestibular schwannoma (VS) resections. METHODS:Retrospective reviews of estimated intraoperative blood loss volume during surgical resection of 50 bevacizumab-treated and 56 bevacizumab-untreated VS from patients with NF2-related schwannomatosis (NF2-SWN). Two index cases are included. Additionally, masked histopathologic examination of tissues from bevacizumab-treated and untreated VS was evaluated. RESULTS:The mean blood loss during VS resection was statistically increased in patients with prior bevacizumab treatment (421 mL) compared to untreated patients (285 mL) (p = 0.015). When accounting for both tumor size and the amount of tumor resected, blood loss per percent of tumor resected was also elevated in the bevacizumab treated group (15.78 mL/%resection) when compared to the untreated group (12.97 mL/%resection) (p = 0.024). Intraoperative hemostasis using standard techniques was difficult, and some cases resulted in early termination of the surgical procedure prior to total resection. Eighteen percent of bevacizumab-treated patients had gross total or near total tumor resection, while untreated tumors had 52% gross total or near total resections (p-value = 0.001). The length of time on bevacizumab preoperatively correlated with intraoperative blood loss (p = 0.049). The median time patients were treated with bevacizumab prior to surgery was 23.5 months and ranged from 3 to 121 months. The median time off bevacizumab prior to surgery was 11.5 months and ranged from 0.75 to 87 months. Histopathologic examination revealed no readily apparent difference in blood vessel density, integrity, or growth patterns. CONCLUSIONS:Bevacizumab treatment prior to excision of NF2-SWN VS in this retrospective case series is associated with increased intraoperative hemorrhage. Bleeding was difficult to control using standard techniques, thus warranting preoperative surgical awareness. Underlying pathologic mechanisms are not yet understood and are under further investigation. LEVEL OF EVIDENCE: 3:

OBJECTIVE(S):Recently directed methods of inner ear drug delivery underscore the necessity for understanding critical anatomical dimensions. This study examines anatomical measurements of the human middle and inner ear relevant for inner ear drug delivery studied with three different imaging modalities. METHODS:Post-mortem human temporal bones were analyzed using human temporal bone histopathology (N = 24), micro computerized tomography (μCT; N = 4), and synchrotron radiation phase-contrast imaging (SR-PCI; N = 7). Nine measurements involving the oval and round windows were performed when relevant anatomical structures were visualized for subsequent age-controlled analysis, and comparisons were made between imaging methods. RESULTS:Combined human temporal bone histopathology showed the mean distance to the saccule from the center of the stapes footplate (FP) was 2.07 ± 0.357 mm and the minimum distance was 1.23 mm. The mean distance from the round window membrane (RWM) to the osseous spiral lamina (OSL) was 1.75 ± 0.199 mm and the minimum distance was 1.43 mm. Instruments inserted up to 1 mm past the center of the FP are unlikely to cause saccular damage, provided there are no endolymphatic hydrops. Similarly, instruments inserted up to 1 mm through the RWM in the trajectory toward the OSL are unlikely to cause OSL damage. CONCLUSION:The combined analyses of inner-ear dimensions of age-controlled groups and imaging modalities demonstrate critical dimensions of importance to consider when inserting delivery vehicles into the human cochlea. LEVEL OF EVIDENCE:N/A Laryngoscope, 134:2879-2888, 2024.

Background Neurofibromatosis type 2-related schwannomatosis is a genetic disease characterized by the development of bilateral vestibular schwannomas, ependymomas, meningiomas, and cataracts. Mild to profound hearing loss and tinnitus are common symptoms reported by individuals with neurofibromatosis type 2. While tinnitus is known to have a significant and negative impact on the quality of life of individuals from the general population, the impact on individuals with neurofibromatosis type 2 is unknown. Consensus regarding the selection of suitable patient-reported outcome measures for assessment could advance further research into tinnitus in neurofibromatosis type 2 patients. The purpose of this work is to achieve a consensus recommendation by the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration for patient-reported outcome measures used to evaluate quality of life in the domain of tinnitus for neurofibromatosis type 2 clinical trials.Methods The Response Evaluation in Neurofibromatosis and Schwannomatosis Patient-Reported Outcomes Communication Subgroup systematically evaluated patient-reported outcome measures of quality of life in the domain of tinnitus for individuals with neurofibromatosis type 2 using previously published Response Evaluation in Neurofibromatosis and Schwannomatosis rating procedures. Of the 19 identified patient-reported outcome measures, 3 measures were excluded because they were not validated as an outcome measure or could not have been used as a single outcome measure for a clinical trial. Sixteen published patient-reported outcome measures for the domain of tinnitus were scored and compared on their participant characteristics, item content, psychometric properties, and feasibility for use in clinical trials.Results The Tinnitus Functional Index was identified as the most highly rated measure for the assessment of tinnitus in populations with neurofibromatosis type 2, due to strengths in the areas of item content, psychometric properties, feasibility, and available scores.Discussion Response Evaluation in Neurofibromatosis and Schwannomatosis currently recommends the Tinnitus Functional Index for the assessment of tinnitus in neurofibromatosis type 2 clinical trials.

Objective To validate how an automated model for vestibular schwannoma (VS) segmentation developed on an external homogeneous dataset performs when applied to internal heterogeneous data. Patients The external dataset comprised 242 patients with previously untreated, sporadic unilateral VS undergoing Gamma Knife radiosurgery, with homogeneous magnetic resonance imaging (MRI) scans. The internal dataset comprised 10 patients from our institution, with heterogeneous MRI scans. Interventions An automated VS segmentation model was developed on the external dataset. The model was tested on the internal dataset. Main Outcome Measure Dice score, which measures agreement between ground truth and predicted segmentations. Results When applied to the internal patient scans, the automated model achieved a mean Dice score of 61% across all 10 images. There were three tumors that were not detected. These tumors were 0.01 ml on average (SD = 0.00 ml). The mean Dice score for the seven tumors that were detected was 87% (SD = 14%). There was one outlier with Dice of 55%—on further review of this scan, it was discovered that hyperintense petrous bone had been included in the tumor segmentation. Conclusions We show that an automated segmentation model developed using a restrictive set of siloed institutional data can be successfully adapted for data from different imaging systems and patient populations. This is an important step toward the validation of automated VS segmentation. However, there are significant shortcomings that likely reflect limitations of the data used to train the model. Further validation is needed to make automated segmentation for VS generalizable.

Objectives This study compared the immune‐related secretory capacity of human vestibular schwannoma (VS) and tumor‐assisted macrophages (TAMs) with their normal counterparts (Schwann cells [SC] and peripheral blood monocyte‐derived macrophages [Mo‐MFs], respectively), and examined relationships with presurgical hearing and tumor size. Methods VS tumors ( n = 16), auditory nerve ( n = 1), blood ( n = 9), and great auricular nerves ( n = 3) were used. SCs (S100B + ) and TAMs (CD68 + ) were isolated from VS tissue for culture. The secreted levels of 65 immune‐related factors were measured and compared using unpaired t ‐tests with Welch correction (schwannoma vs. SCs) or Mann–Whitney tests (TAMs and Mo‐MFs). Associations between factor concentration and word recognition (WR), pure‐tone average (PTA), and tumor size were evaluated with Spearman correlation. Results Secreted factors with significantly higher concentrations in schwannoma versus SC supernatants included IL‐2 and BAFF, whereas MMP‐1, IL‐6, FGF‐2, VEGF‐A, MIP‐3α, and GRO‐α concentrations were significantly higher in TAMs versus Mo‐MFs (all p < 0.05). Worse WR was significantly associated with higher secretion of fractalkine, eotaxin‐3, CD30, and IL‐16 by VS cells; IP‐10, eotaxin‐3, multiple interleukins, GM‐CSF, SCF, and CD30 by TAMs; and TNF‐α and MIP‐1α by Mo‐MFs (all p < 0.05). Worse PTA was significantly correlated with higher secretion of IL‐16 by VS cells ( p < 0.05). Larger tumor size was significantly correlated with higher secretion of eotaxin by VS cells, and of IL‐7, IL‐21, and LIF by TAMs (all p = 0.017). Conclusions Differential secretion of immune‐related factors was observed in schwannoma versus normal SCs and in TAMs versus Mo‐MFs, some of which were correlated with worse hearing and larger VS tumors. Level of Evidence N/A Laryngoscope , 134:S1–S14, 2024

(1) Background: This study aimed to evaluate the efficacy and treatment-related toxicity of proton radiotherapy (PRT) for vestibular schwannoma (VS) in patients with neurofibromatosis type 2-related schwannomatosis (NF2). (2) Methods: Consecutive NF2 patients treated with PRT for VS between 2004 and 2016 were retrospectively evaluated, focusing on tumor volume, facial and trigeminal nerve function, hearing, tinnitus, vestibular symptoms, and the need for salvage therapy after PRT. (3) Results: Eight patients were included (median age 36 years, 50% female). Median follow-up was 71 months. Five (63%) patients received fractionated PRT and three (38%) received PRT radiosurgery for VS. Six patients (75%) received prior VS surgery; three also received bevacizumab. Six patients (75%) did not require salvage therapy after PRT. Two patients (25%) with residual hearing lost it after PRT, and six had already lost ipsilateral hearing prior to PRT. Tumor and treatment-related morbidity could be evaluated in six patients. Following PRT, conditions that occurred or worsened were: facial paresis in five (83%), trigeminal hypoesthesia in two (33%), tinnitus in two (33%), and vestibular symptoms in four patients (67%). (4) Conclusion: After PRT for VS, the majority of the NF2 patients in the cohort did not require additional therapy. Tumor and/or treatment-related cranial nerve deficits were common. This is at least partly explained by the use of PRT as a salvage treatment after surgery or bevacizumab, in the majority of cases. There remains the further opportunity to elucidate the efficacy and toxicity of proton radiotherapy as a primary treatment.

ImportancePersistent tinnitus is common, disabling, and difficult to treat.ObjectiveTo evaluate the association between circulating metabolites and persistent tinnitus.Design, Setting, and ParticipantsThis was a population-based case-control study of 6477 women who were participants in the Nurses’ Health Study (NHS) and NHS II with metabolomic profiles and tinnitus data. Information on tinnitus onset and frequency was collected on biennial questionnaires (2009-2017). For cases, metabolomic profiles were measured (2015-2021) in blood samples collected after the date of the participant’s first report of persistent tinnitus (NHS, 1989-1999 and 2010-2012; NHS II, 1996-1999). Data analyses were performed from January 24, 2022, to January 14, 2023.ExposuresIn total, 466 plasma metabolites from 488 cases of persistent tinnitus and 5989 controls were profiled using 3 complementary liquid chromatography tandem mass spectrometry approaches.Main Outcomes and MeasuresLogistic regression was used to estimate odds ratios (ORs) of persistent tinnitus (per 1 SD increase in metabolite values) and 95% CIs for each individual metabolite. Metabolite set enrichment analysis was used to identify metabolite classes enriched for associations with tinnitus.ResultsOf the 6477 study participants (mean [SD] age, 52 [9] years; 6477 [100%] female; 6121 [95%] White individuals) who were registered nurses, 488 reported experiencing daily persistent (≥5 minutes) tinnitus. Compared with participants with no tinnitus (5989 controls), those with persistent tinnitus were slightly older (53.0 vs 51.8 years) and more likely to be postmenopausal, using oral postmenopausal hormone therapy, and have type 2 diabetes, hypertension, and/or hearing loss at baseline. Compared with controls, homocitrulline (OR, 1.32; (95% CI, 1.16-1.50); C38:6 phosphatidylethanolamine (PE; OR, 1.24; 95% CIs, 1.12-1.38), C52:6 triglyceride (TAG; OR, 1.22; 95% CIs, 1.10-1.36), C36:4 PE (OR, 1.22; 95% CIs, 1.10-1.35), C40:6 PE (OR, 1.22; 95% CIs, 1.09-1.35), and C56:7 TAG (OR, 1.21; 95% CIs, 1.09-1.34) were positively associated, whereas α-keto-β-methylvalerate (OR, 0.68; 95% CIs, 0.56-0.82) and levulinate (OR, 0.60; 95% CIs, 0.46-0.79) were inversely associated with persistent tinnitus. Among metabolite classes, TAGs (normalized enrichment score [NES], 2.68), PEs (NES, 2.48), and diglycerides (NES, 1.65) were positively associated, whereas phosphatidylcholine plasmalogens (NES, −1.91), lysophosphatidylcholines (NES, −2.23), and cholesteryl esters (NES,−2.31) were inversely associated with persistent tinnitus.Conclusions and RelevanceThis population-based case-control study of metabolomic profiles and tinnitus identified novel plasma metabolites and metabolite classes that were significantly associated with persistent tinnitus, suggesting that metabolomic studies may help improve understanding of tinnitus pathophysiology and identify therapeutic targets for this challenging disorder.

Hintergrund Neurofibromatose Typ 2 (NF2) ist assoziiert mit Verlust von NF2/Merlin, was zu Schwannomen des Vestibularnerven und kochleärer Schwerhörigkeit (SNHL) führen kann. Die ätiologie des Hörverlusts ist bis zum heutigen Tag nicht vollständig geklärt, gängige Studien vermuten Sekretion von pro-inflammatorischen und neurotoxischen Substanzen als Ursache. In dieser Studie untersuchten wir auditorische und vestibuläre Nerven und Gliazellen in einem Mausmodell für NF2, um den kochleären Phänotyp besser zu beschreiben.

PDF file - 1.6MB, S1. The predicted truncated merlin protein was not detected in Ben-Men-1 cells. S2. IC50 determination of AR-42 in normal meningeal cells. S3. AR-42 treatment increased protein acetylation and decreased p-AKT. S4. Normal meningeal cells proliferate with a doubling time of about three days. S5. Ben-Men-1-LucB and parental Ben-Men-1 cells exhibit similar sensitivities to AR-42. S6. Intracranial NF2-deficient KT21-MG1 xenograft tumors demonstrated features of malignant meningiomas. S7. Ben-Men-1-LucB xenografts strongly expressed vimentin, amesenchymal marker for meningiomas. S8. AR-42 treatment caused tumor regression, whereas AR-12 treatment slowed tumor growth over time. S9. MRI detected a small tumor in a Ben-Men-1-LucB tumorbearing mouse treated with AR-42 for three months. S10. MRI did not detect the residual tumor in an AR-42-treated mouse after removal from AR-42 diet for six months.

Abstract NF2–related schwannomatosis is a genetic disorder characterized by neurologic tumours, most typically vestibular schwannomas that originate on the vestibulo-cochlear nerve(s). Although vestibular symptoms can be disabling, vestibular function has never been carefully analysed in NF2–related schwannomatosis. Furthermore, chemotherapy (e.g. bevacizumab) can reduce tumour volume and improve hearing in NF2–related schwannomatosis, but nothing is known about its vestibular effects. In this report, we studied the three primary vestibular-mediated behaviours (eye movements, motion perception and balance), clinical vestibular disability (dizziness and ataxia), and imaging and hearing in eight untreated patients with NF2–related schwannomatosis and compared their results with normal subjects and patients with sporadic, unilateral vestibular schwannoma tumours. We also examined how bevacizumab affected two patients with NF2–related schwannomatosis. Vestibular schwannomas in NF2–related schwannomatosis degraded vestibular precision (inverse of variability, reflecting a reduced central signal-to-noise ratio) but not vestibular accuracy (amplitude relative to ideal amplitude, reflecting the central signal magnitude) and caused clinical disability. Bevacizumab improved vestibular precision and clinical disability in both patients with NF2–related schwannomatosis but did not affect vestibular accuracy. These results demonstrate that vestibular schwannoma tumours in our NF2–related schwannomatosis population degrade the central vestibular signal-to-noise ratio, while bevacizumab improves the signal-to-noise ratio, changes that can be explained mechanistically by the addition (schwannoma) and suppression (bevacizumab) of afferent neural noise.

Importance Persistent tinnitus is common, disabling, and difficult to treat. Objective To evaluate the association between circulating metabolites and persistent tinnitus. Design, Setting, and Participants This was a population-based case-control study of 6477 women who were participants in the Nurses' Health Study (NHS) and NHS II with metabolomic profiles and tinnitus data. Information on tinnitus onset and frequency was collected on biennial questionnaires (2009-2017). For cases, metabolomic profiles were measured (2015-2021) in blood samples collected after the date of the participant's first report of persistent tinnitus (NHS, 1989-1999 and 2010-2012; NHS II, 1996-1999). Data analyses were performed from January 24, 2022, to January 14, 2023. Exposures In total, 466 plasma metabolites from 488 cases of persistent tinnitus and 5989 controls were profiled using 3 complementary liquid chromatography tandem mass spectrometry approaches. Main Outcomes and Measures Logistic regression was used to estimate odds ratios (ORs) of persistent tinnitus (per 1 SD increase in metabolite values) and 95% CIs for each individual metabolite. Metabolite set enrichment analysis was used to identify metabolite classes enriched for associations with tinnitus. Results Of the 6477 study participants (mean [SD] age, 52 [9] years; 6477 [100%] female; 6121 [95%] White individuals) who were registered nurses, 488 reported experiencing daily persistent (≥5 minutes) tinnitus. Compared with participants with no tinnitus (5989 controls), those with persistent tinnitus were slightly older (53.0 vs 51.8 years) and more likely to be postmenopausal, using oral postmenopausal hormone therapy, and have type 2 diabetes, hypertension, and/or hearing loss at baseline. Compared with controls, homocitrulline (OR, 1.32; (95% CI, 1.16-1.50); C38:6 phosphatidylethanolamine (PE; OR, 1.24; 95% CIs, 1.12-1.38), C52:6 triglyceride (TAG; OR, 1.22; 95% CIs, 1.10-1.36), C36:4 PE (OR, 1.22; 95% CIs, 1.10-1.35), C40:6 PE (OR, 1.22; 95% CIs, 1.09-1.35), and C56:7 TAG (OR, 1.21; 95% CIs, 1.09-1.34) were positively associated, whereas α-keto-β-methylvalerate (OR, 0.68; 95% CIs, 0.56-0.82) and levulinate (OR, 0.60; 95% CIs, 0.46-0.79) were inversely associated with persistent tinnitus. Among metabolite classes, TAGs (normalized enrichment score [NES], 2.68), PEs (NES, 2.48), and diglycerides (NES, 1.65) were positively associated, whereas phosphatidylcholine plasmalogens (NES, -1.91), lysophosphatidylcholines (NES, -2.23), and cholesteryl esters (NES,-2.31) were inversely associated with persistent tinnitus. Conclusions and Relevance This population-based case-control study of metabolomic profiles and tinnitus identified novel plasma metabolites and metabolite classes that were significantly associated with persistent tinnitus, suggesting that metabolomic studies may help improve understanding of tinnitus pathophysiology and identify therapeutic targets for this challenging disorder.

Vestibular schwannoma (VS) is an intracranial tumor arising from neoplastic Schwann cells and typically presenting with hearing loss. The traditional belief that hearing deficit is caused by physical expansion of the VS, compressing the auditory nerve, does not explain the common clinical finding that patients with small tumors can have profound hearing loss, suggesting that tumor-secreted factors could influence hearing ability in VS patients. We conducted profiling of patients' plasma for 66 immune-related factors in patients with sporadic VS (N > 170) and identified and validated candidate biomarkers associated with tumor size (S100B) and hearing (MCP-3). We further identified a nine-biomarker panel (TNR-R2, MIF, CD30, MCP-3, IL-2R, BLC, TWEAK, eotaxin, and S100B) with outstanding discriminatory ability for VS. These findings revealed possible therapeutic targets for VS, providing a unique diagnostic tool that may predict hearing change and tumor growth in VS patients, and may inform the timing of tumor resection to preserve hearing.