Interaural and sex differences in the natural evolution of hearing levels in pre-symptomatic and symptomatic carriers of the p.Pro51Ser variant in the COCH gene.

Hearing impairment constitutes a significant health problem in developed countries. If hearing loss is slowly progressive, the first signs may not be noticed in time, or remain untreated until the moment the auditory dysfunction becomes more apparent. The present study will focus on DFNA9, an autosomal dominant disorder caused by pathogenic variants in the COCH gene. Although several cross-sectional studies on this topic have been conducted, a crucial need for longitudinal research has been reported by many authors. Longitudinal trajectories of individual hearing thresholds were established as function of age and superimposed lowess curves were generated for 101 female and male carriers of the p.Pro51Ser variant. The average number of times patients have been tested was 2.49 years with a minimum of 1 year and a maximum of 4 years. In addition, interaural and sex differences were studied, as they could modify the natural evolution of the hearing function. The current study demonstrates that, both in female carriers and male carriers, the first signs of hearing decline, i.e. hearing thresholds of 20 dB HL, become apparent as early as the 3rd decade in the highest frequencies. In addition, a rapid progression of SNHL occurs between 40 and 50 years of age. Differences between male and female carriers in the progression of hearing loss are most obvious between the age of 50 and 65 years. Furthermore, interaural discrepancies also manifest from the age of 50 years onwards. High-quality prospective data on the long-term natural evolution of hearing levels offer the opportunity to identify different disease stages in each cochlea and different types of evolution. This will provide more insights in the window of opportunity for future therapeutic intervention trials.

Rational design of a genomically humanized mouse model for dominantly inherited hearing loss, DFNA9.

DFNA9 is a dominantly inherited form of adult-onset progressive hearing impairment caused by mutations in the COCH gene. COCH encodes cochlin, a crucial extracellular matrix protein. We established a genomically humanized mouse model for the Dutch/Belgian c.151C>T founder mutation in COCH. Considering upcoming sequence-specific genetic therapies, we exchanged the genomic murine Coch exons 3-6 for the corresponding human sequence. Introducing human-specific genetic information into mouse exons can be risky. To mitigate unforeseen consequences on cochlin function resulting from the introduction of the human COCH protein-coding sequence, we converted all human-specific amino acids to mouse equivalents. We furthermore optimized the recognition of the human COCH exons by the murine splicing machinery during pre-mRNA splicing. Subsequent observations in mouse embryonic stem cells revealed correct splicing of the hybrid Coch transcript. The inner ear of the established humanized Coch mice displays correctly-spliced wild-type and mutant humanized Coch alleles. For a comprehensive study of auditory function, mice were crossbred with C57BL/6 Cdh23753A>G mice to remove the Cdh23ahl allele from the genetic background of the mice. At 9 months, all humanized Coch genotypes showed hearing thresholds comparable to wild-type C57BL/6 Cdh23753A>G mice. This indicates that both the introduction of human wildtype COCH, and correction of Cdh23ahl in the humanized Coch lines was successful. Overall, our approach proved beneficial in eliminating potential adverse events of genomic humanization of mouse genes, and provides us with a model in which sequence-specific therapies directed against the human mutant COCH alle can be investigated. With the hearing and balance defects anticipated to occur late in the second year of life, a long-term follow-up study is ongoing to fully characterize the humanized Coch mouse model.

Evidence of Vestibular and Balance Dysfunction in Patients With Mild Cognitive Impairment and Alzheimer's Disease.

OBJECTIVES: Given the expected rise in dementia prevalence, early diagnosis is vital. As a growing body of literature has identified a potential association between vestibular function and cognition, vestibular assessment may aid in early screening. The aim of the study was to better comprehend the proposed association between vestibular function and Alzheimer's disease (AD) by comparing vestibular parameters (vestibular function testing and clinical balance measures) between a group with mild cognitive impairment (MCI), AD, and healthy controls with age-normal cognition. DESIGN: Cross-sectional analysis of the GECkO study, an ongoing prospective single-center longitudinal cohort study. This study included 100 older adults (55 to 84 years). A total of 33 participants with MCI, 17 participants with AD, and 50 participants of age, sex, and hearing-matched healthy controls were included. RESULTS: Participants with AD demonstrated a delayed latency of the p13 component measured by cervical vestibular-evoked myogenic potentials (cVEMP) compared with healthy controls and participants with MCI. Other measures including n23 latency, presence of intact responses, rectified amplitude, mean rectified voltage (measured by cVEMP) and lateral vestibulo-ocular reflex gain (measured by video Head Impulse Test [vHIT]) did not differ between groups. The Timed Up and Go (TUG), Performance-Oriented Mobility Assessment-Balance subscale (POMA-B), and Functional Gait Assessment (FGA) differed significantly between the three groups. Here, more cognitively impaired groups were associated with worse clinical balance scores. CONCLUSIONS: Vestibular and balance deficits were more prevalent in groups with increasing cognitive decline. Regarding vestibular function testing, p13 latency as measured by cVEMP was delayed in participants with AD. Other cVEMP or vHIT measures did not differ between groups. All three clinical balance assessments (TUG, POMA-B, and FGA) resulted in worse scores along the AD continuum. Future research integrating vestibular parameters that add value (including otolith function testing, balance, and spatial navigation) is recommended to validate the association between vestibular function and cognition while avoiding redundant testing.

Is vestibular function related to human hippocampal volume?

BACKGROUND: Recent studies implicate the effect of vestibular loss on cognitive decline, including hippocampal volume loss. As hippocampal atrophy is an important biomarker of Alzheimer's disease, exploring vestibular dysfunction as a risk factor for dementia and its role in hippocampal atrophy is of interest. OBJECTIVE: To replicate previous literature on whole-brain and hippocampal volume in semicircular canal dysfunction (bilateral vestibulopathy; BV) and explore the association between otolith function and hippocampal volume. METHODS: Hippocampal and whole-brain MRI volumes were compared in adults aged between 55 and 83 years. Participants with BV (n = 16) were compared to controls individually matched on age, sex, and hearing status (n = 16). Otolith influence on hippocampal volume in preserved semicircular canal function was evaluated (n = 34). RESULTS: Whole-brain and targeted hippocampal approaches using volumetric and surface-based measures yielded no significant differences when comparing BV to controls. Binary support vector machines were unable to classify inner ear health status above chance level. Otolith parameters were not associated with hippocampal volume in preserved semicircular canal function. CONCLUSIONS: No significant differences in whole-brain or hippocampal volume were found when comparing BV participants with healthy controls. Saccular parameters in subjects with preserved semicircular canal function were not associated with hippocampal volume changes.

Evaluation of hearing levels and vestibular function and the impact on cognitive performance in (pre)-symptomatic patients with DFNA9: protocol for a prospective longitudinal study (Rosetta study).

INTRODUCTION: Untreated hearing loss is the largest potentially modifiable risk factor for dementia. Additionally, vestibular dysfunction has been put forward as a potential risk factor for accelerated cognitive decline. Patients with Deafness Autosomal Dominant 9 (DFNA9) present with progressive sensorineural hearing loss and bilateral vestibulopathy and show significantly worse results in cognitive performance compared with a cognitively healthy control group. This highlights the need for adequate treatment to prevent further cognitive decline. This study aims to determine how hearing and vestibular function evolve in (pre-)symptomatic carriers of the p.Pro51Ser mutation in the COCH gene and how this impacts their cognitive performance and health-related quality of life. METHODS AND ANALYSIS: A prospective, longitudinal evaluation of hearing, vestibular function and cognitive performance will be acquired at baseline, 1-year and 2-year follow-up. A total of 40 patients with DFNA9 will be included in the study. The study will be a single-centre study performed at the ORL department at the Antwerp University Hospital (UZA), Belgium. The control group will encompass cognitively healthy subjects, already recruited through the GECkO study. The primary outcome measure will be the Repeatable Battery for the Assessment of Neuropsychological Status adjusted for the Hearing-Impaired total score. Secondary outcome measures include Cortical Auditory-Evoked Potentials, vestibular assessments and health-related quality of life questionnaires. The expected outcomes will aid in the development of gene therapy by providing insight in the optimal time window for the application of gene therapy for the inner ear. ETHICS AND DISSEMINATION: The ethical committee of UZA approved the study protocol on 19 December 2022 (protocol number B3002022000170). All participants have to give written initial informed consent in accordance with the Declaration of Helsinki. Results will be disseminated to the public through conference presentations, lectures and peer-reviewed scientific publications.

Accelerated Cognitive Decline Associated With Hearing Loss and Bilateral Vestibulopathy: Insights From a Prospective Cross-Sectional Study Using the Repeatable Battery for the Assessment of Neuropsychological Status Adjusted for the Hearing Impaired in the DFNA9 Population.

BACKGROUND: DeaFNess Autosomal dominant 9 (DFNA9) is a hereditary disorder known to affect both hearing and vestibular function in its carriers. Its phenotype is characterized by progressive sensorineural hearing loss (SNHL) and vestibular dysfunction evolving towards bilateral vestibulopathy (BV) by the 3rd to 5th life decade. Recent studies have identified the impact of hearing loss and vestibular dysfunction on cognitive functioning. OBJECTIVE: The main objective of this study was to investigate how the cognitive functioning of carriers of the p.Pro51Ser variant in the COCH gene is affected by the disease and compare these results with a matched healthy control group. STUDY DESIGN: Forty-six carriers of the pathogenic p.Pro51Ser variant in the COCH gene were included in this study, of which 38 met the Bárány Society criteria and were thus diagnosed with BV. All subjects were between the age of 22 and 72 years old. Each control was individually matched based on age, gender, and education level. A cognitive, vestibular, and hearing assessment was performed in all subjects. All participants completed the Repeatable Battery for the Assessment of Neuropsychological Status, adjusted for the Hearing Impaired (RBANS-H), a cognitive test battery that includes subtests probing Immediate and Delayed Memory, Visuospatial/Constructional, Language, and Attention. RESULTS: Overall, the DFNA9 patients demonstrated significantly lower scores on the Immediate Memory subscale and lower Total Scale scores than their healthy matched controls. The total sample was divided into two groups: age <55 years old and age ≥55 years old. The DFNA9 group aged ≥55 years old obtained significantly lower scores on the Attention subscale and lower Total Scale scores than their matched controls. Cognition of DFNA9 patients aged <55 years old no longer differed significantly from their matched controls. CONCLUSION: This cross-sectional study found that DFNA9 patients demonstrated cognitive deficits in comparison with their healthy matched controls. The DFNA9 group aged ≥ 55 years old obtained significantly lower scores on the Total Scale and Attention subscale. This finding; however, was not observed for the age group younger than 55 years old. Further research is needed on the individual trajectory of SNHL and vestibular function, and how hearing rehabilitation affects cognitive functioning.

Associations of Bilateral Vestibulopathy With Cognition in Older Adults Matched With Healthy Controls for Hearing Status.

Importance: Recent literature suggests there may be a significant effect of the vestibular system on cognition and visuospatial processing. Given the increasing prevalence of dementia and individuals at risk for it, exploring possible modifiable risk factors, including vestibular dysfunction, is vital. Objectives: To explore the association of bilateral vestibulopathy (BV) with cognitive function in older adults, taking hearing status into account, and to explore multiple vestibular characteristics and their potential associations with cognition in patients with BV. Design, Setting, and Participants: This cross-sectional study assessed older adults (age 55-84 years) with diagnosed BV from a single center using baseline measurements from the Gehoor, Evenwicht en Cognitie (GECKO) study, an ongoing prospective longitudinal cohort study. Each participant was individually matched with a healthy control based on age, sex, and hearing performance. Data were analyzed in January 2022. Main Outcomes and Measures: The primary outcome measure was cognition, measured by the Repeatable Battery for the Assessment of Neuropsychological Status for Hearing-Impaired Individuals (RBANS-H). Results: A total of 68 patients were assessed, including 34 patients with BV (mean [SD] age, 63.3 [6.0] years; 18 [53%] men) matched with 34 control individuals without BV. Overall, participants with BV had a clinically meaningful lower score on the RBANS-H total scale compared with those without BV (mean [SD] score, 98.62 [12.70] vs 105.91 [11.03]). This decline was most pronounced in the subdomains of immediate memory (mean [SD] score, 107.74 [10.66] vs 112.26 [10.66]), visuospatial cognition (mean [SD] score, 90.06 [13.34] vs 100.47 [13.91]), and attention (mean [SD] score, 94.79 [16.39] vs 102.06 [12.97]). There were no differences in language or delayed memory subdomains. Within the BV population, 1 vestibular parameter (the Performance-Oriented Mobility Assessment, in particular the balance subscale) was associated with lower cognitive scores (r32 = 0.51; 95% CI, 0.20 to 0.72; η2 = 0.26). Other vestibular parameters, including measurements of the peripheral vestibular end organ and questionnaires, showed no association. Conclusions and Relevance: These findings suggest there was an association between vestibular loss and cognitive impairment. Further research on the causal mechanisms underlying this association and the possible impact of vestibular rehabilitation on cognition is needed.

Cortical Auditory Evoked Potentials in Cognitive Impairment and Their Relevance to Hearing Loss: A Systematic Review Highlighting the Evidence Gap.

Background: Alzheimer's disease (AD) is the most prevalent cause of dementia which affects a growing number of people worldwide. Early identification of people at risk to develop AD should be prioritized. Hearing loss is considered an independent potentially modifiable risk factor for accelerated cognitive decline and dementia in older adults. The main outcome of interest of this review is the alteration of Cortical Auditory Evoked Potential (CAEP) morphology in an AD or mild cognitive impairment (MCI) population with and without hearing loss. Methods: Two investigators independently and systematically searched publications regarding auditory processing on a cortical level in people with cognitive impairment (MCI or AD) with and without hearing loss. Only articles which mentioned at least one auditory elicited event-related potential (ERP) component and that were written in English or Dutch were included. Animal studies were excluded. No restrictions were imposed regarding publication date. The reference list of potential sources were screened for additional articles. Results: This systematic review found no eligible articles that met all inclusion criteria. Therefore, no results were included, resulting in an empty systematic review. Conclusion: In general, dysfunction - being either from cognitive or auditory origin - reduces CAEP amplitudes and prolongs latencies. Therefore, CAEPs may be a prognostic indicator in the early stages of cognitive decline. However, it remains unclear which CAEP component alteration is due to cognitive impairment, and which is due to hearing loss (or even both). In addition, vestibular dysfunction - associated with hearing loss, cognitive impairment and AD - may also alter CAEP responses. Further CAEP studies are warranted, integrating cognitive, hearing, and vestibular evaluations.