A Combination Antioxidant Therapy in the Treatment and Prevention of Age Related Hearing Loss

University of Minnesota Ph.D. dissertation. July 2015. Major: Otolaryngology. Advisors: Rick Odland, Steven Juhn. 1 computer file (PDF); vi, 159 pages.Presbycusis, or age-related hearing loss, is one of the most common conditions impacting the aging population, characterized by progressive sensorineural hearing loss and impairment in speech discrimination capability. Current management is limited to auditory rehabilitation with the assistance of hearing aids or cochlear implants in advanced cases. There currently exists no effective treatments available for the prevention or attenuation of hearing loss in association with presbycusis. The purpose of this study was to evaluate the potential of a combination antioxidant therapy in the prevention and treatment of presbycusis. The objectives of this randomized controlled animal study were to: identify an anesthetic which would allow for repeated reliable longitudinal auditory brainstem response (ABR) testing in a mouse model, identify a combination antioxidant which targets multiple sites within the oxidative pathway and assess its ability to prevent age-related threshold shifts and to arrest further age-related threshold shifts in C57BL6 mice with documented age-related threshold shifts. Mice were randomized to one of three groups: an early treatment group, a late treatment group, or a control group. The treatment groups of mice were fed with a combination agent comprised 6 antioxidant agents. ABRs were performed comparing Avertin to ketamine/xylazine with no significant difference in test thresholds. ABR thresholds were recorded at baseline and every 3 months following initiation of treatment in the 3 randomized groups. Threshold shifts from baseline were decreased in the treatment groups when compared to the control group at all tested frequencies and time points.Presbycusis, or age-related hearing loss, is one of the most common conditions impacting the aging population, characterized by progressive sensorineural hearing loss and impairment in speech discrimination capability. Current management is limited to auditory rehabilitation with the assistance of hearing aids or cochlear implants in advanced cases. There currently exists no effective treatments available for the prevention or attenuation of hearing loss in association with presbycusis. The purpose of this study was to evaluate the potential of a combination antioxidant therapy in the prevention and treatment of presbycusis. The objectives of this randomized controlled animal study were to: identify an anesthetic which would allow for repeated reliable longitudinal auditory brainstem response (ABR) testing in a mouse model, identify a combination antioxidant which targets multiple sites within the oxidative pathway and assess its ability to prevent age-related threshold shifts and to arrest further age-related threshold shifts in C57BL6 mice with documented age-related threshold shifts. Mice were randomized to one of three groups: an early treatment group, a late treatment group, or a control group. The treatment groups of mice were fed with a combination agent comprised 6 antioxidant agents. ABRs were performed comparing Avertin to ketamine/xylazine with no significant difference in test thresholds. ABR thresholds were recorded at baseline and every 3 months following initiation of treatment in the 3 randomized groups. Threshold shifts from baseline were decreased in the treatment groups when compared to the control group at all tested frequencies and time points

Precision Modulation of Neurodegenerative Disease-Related Gene Expression in Human iPSC-Derived Neurons

The ability to reprogram adult somatic cells into induced pluripotent stem cells (iPSCs) and the subsequent development of protocols for their differentiation into disease-relevant cell types have enabled in-depth molecular analyses of multiple disease states as hitherto impossible. Neurons differentiated from patient-specific iPSCs provide a means to recapitulate molecular phenotypes of neurodegenerative diseases in vitro. However, it remains challenging to conduct precise manipulations of gene expression in iPSC-derived neurons towards modeling complex human neurological diseases. The application of CRISPR/Cas9 to mammalian systems is revolutionizing the utilization of genome editing technologies in the study of molecular contributors to the pathogenesis of numerous diseases. Here, we demonstrate that CRISPRa and CRISPRi can be used to exert precise modulations of endogenous gene expression in fate-committed iPSC-derived neurons. This highlights CRISPRa/i as a major technical advancement in accessible tools for evaluating the specific contributions of critical neurodegenerative disease-related genes to neuropathogenesis

Comparison of the gene expression profiles of human fetal cortical astrocytes with pluripotent stem cell derived neural stem cells identifies human astrocyte markers and signaling pathways and transcription factors active in human astrocytes

Astrocytes are the most abundant cell type in the central nervous system (CNS) and have a multitude of functions that include maintenance of CNS homeostasis, trophic support of neurons, detoxification, and immune surveillance. It has only recently been appreciated that astrocyte dysfunction is a primary cause of many neurological disorders. Despite their importance in disease very little is known about global gene expression for human astrocytes. We have performed a microarray expression analysis of human fetal astrocytes to identify genes and signaling pathways that are important for astrocyte development and maintenance. Our analysis confirmed that the fetal astrocytes express high levels of the core astrocyte marker GFAP and the transcription factors from the NFI family which have been shown to play important roles in astrocyte development. A group of novel markers were identified that distinguish fetal astrocytes from pluripotent stem cell-derived neural stem cells (NSCs) and NSC-derived neurons. As in murine astrocytes, the Notch signaling pathway appears to be particularly important for cell fate decisions between the astrocyte and neuronal lineages in human astrocytes. These findings unveil the repertoire of genes expressed in human astrocytes and serve as a basis for further studies to better understand astrocyte biology, especially as it relates to disease.published_or_final_versio

Cepstral peak prominence: a comprehensive analysis

An analytical study of cepstral peak prominence (CPP) is presented, intended to provide an insight into its meaning and relation with voice perturbation parameters. To carry out this analysis, a parametric approach is adopted in which voice production is modelled using the traditional source-filter model and the first cepstral peak is assumed to have Gaussian shape. It is concluded that the meaning of CPP is very similar to that of the first rahmonic and some insights are provided on its dependence with fundamental frequency and vocal tract resonances. It is further shown that CPP integrates measures of voice waveform and periodicity perturbations, be them either amplitude, frequency or noise

Cepstral analysis of hypokinetic and ataxic voices : correlations with perceptual and other acoustic measures

To investigate the validity of cepstral analyses against other conventional acoustic measures of voice quality in determining the perceptual impression in different motor speech disorders—hypokinetic and ataxic dysarthria, and speech tasks—prolonged vowels and connected speech. Prolonged vowel productions and connected speech samples (reading passages and monologues) from 43 participants with Parkinson disease and 10 speakers with ataxia were analyzed perceptually by a trained listener using GRBAS. In addition, acoustic measures of cepstral peak prominence (CPP), smoothed CPP (CPPs), harmonics-to-noise ratio (HNR), shimmer %, shimmer dB, amplitude perturbation quotient (APQ), relative average perturbation (RAP), jitter, and pitch perturbation quotient (PPQ) were performed. Statistical analysis involved correlations between perceptual and acoustic measures, as well as determination of differences across speaker groups and elicitation tasks. CPP and CPPs results showed greater levels of correlation with overall dysphonia, breathiness, and asthenia ratings than the other acoustic measures, except in the case of roughness. Sustained vowel production produced a higher number of significant correlations across all parameters other than connected speech, but task choice did not affect CPP and CPPs results. There were no significant differences in any parameters across the two speaker groups. The results of this study are consistent with the results of other studies investigating the same measures in speakers with nonmotor-related voice pathologies. In addition, there was an indication that they performed better in relation to asthenia, which might be particularly relevant for the current speaker group. The results support the clinical and research use of CPP and CPPs as a quantitative measure of voice quality in populations with motor speech disorder

Automatic Rating of Hoarseness by Text-based Cepstral and Prosodic Evaluation

The standard for the analysis of distorted voices is perceptual rating of read-out texts or spontaneous speech. Automatic voice evaluation, however, is usually done on stable sections of sustained vowels. In this paper, text-based and established vowel-based analysis are compared with respect to their ability to measure hoarseness and its subclasses. 73 hoarse patients (48.3±16.8 years) uttered the vowel /e/ and read the German version of the text “The North Wind and the Sun”. Five speech therapists and physicians rated roughness, breathiness, and hoarseness according to the German RBH evaluation scheme. The best human-machine correlations were obtained for measures based on the Cepstral Peak Prominence (CPP; up to |r | = 0.73). Support Vector Regression (SVR) on CPP-based measures and prosodic features improved the results further to r ≈0.8 and confirmed that automatic voice evaluation should be performed on a text recording

Laryngeal Reinnervation Using Ansa Cervicalis for Thyroid Surgery-Related Unilateral Vocal Fold Paralysis: A Long-Term Outcome Analysis of 237 Cases

To evaluate the long-term efficacy of delayed laryngeal reinnervation using the main branch of the ansa cervicalis in treatment of unilateral vocal fold paralysis (UVFP) caused by thyroid surgery.UVFP remains a serious complication of thyroid surgery. Up to now, a completely satisfactory surgical treatment of UVFP has been elusive.From Jan. 1996 to Jan. 2008, a total of 237 UVFP patients who underwent ansa cervicalis main branch-to-recurrent laryngeal nerve (RLN) anastomosis were enrolled as UVFP group; another 237 age- and gender-matched normal subjects served as control group. Videostroboscopy, vocal function assessment (acoustic analysis, perceptual evaluation and maximum phonation time), and electromyography were performed preoperatively and postoperatively. The mean follow-up period was 5.2±2.7 years, ranging from 2 to 12 years.>0.05, respectively). Postoperative laryngeal electromyography confirmed successful reinnervation of laryngeal muscle.Delayed laryngeal reinnervation with the main branch of ansa cervicalis is a feasible and effective approach for treatment of thyroid surgery-related UVFP; it can restore the physiological laryngeal phonatory function to the normal or a nearly normal voice quality

Pediatric cochlear implantation: an update

Deafness in pediatric age can adversely impact language acquisition as well as educational and social-emotional development. Once diagnosed, hearing loss should be rehabilitated early; the goal is to provide the child with maximum access to the acoustic features of speech within a listening range that is safe and comfortable. In presence of severe to profound deafness, benefit from auditory amplification cannot be enough to allow a proper language development. Cochlear implants are partially implantable electronic devices designed to provide profoundly deafened patients with hearing sensitivity within the speech range. Since their introduction more than 30 years ago, cochlear implants have improved their performance to the extent that are now considered to be standard of care in the treatment of children with severe to profound deafness. Over the years patient candidacy has been expanded and the criteria for implantation continue to evolve within the paediatric population. The minimum age for implantation has progressively reduced; it has been recognized that implantation at a very early age (12–18 months) provides children with the best outcomes, taking advantage of sensitive periods of auditory development. Bilateral implantation offers a better sound localization, as well as a superior ability to understand speech in noisy environments than unilateral cochlear implant. Deafened children with special clinical situations, including inner ear malformation, cochlear nerve deficiency, cochlear ossification, and additional disabilities can be successfully treated, even thogh they require an individualized candidacy evaluation and a complex post-implantation rehabilitation. Benefits from cochlear implantation include not only better abilities to hear and to develop speech and language skills, but also improved academic attainment, improved quality of life, and better employment status. Cochlear implants permit deaf people to hear, but they have a long way to go before their performance being comparable to that of the intact human ear; researchers are looking for more sophisticated speech processing strategies as well as a more efficient coupling between the electrodes and the cochlear nerve with the goal of dramatically improving the quality of sound of the next generation of implants