Reorganized Brain White Matter in Early- and Late-Onset Deafness With Diffusion Tensor Imaging.

OBJECTIVES: Individuals with early- and late-onset deafness showed different functional and morphological brain changes, but white matter alterations in both deaf groups still need to be elucidated. This study aimed to investigate changes in white matter integrity and white matter anatomical connectivity in both early- and late-onset deaf groups compared with hearing group. DESIGN: Diffusion tensor imaging data from 7 early-onset deaf (50.7 ± 6.5 years), 11 late-onset deaf (50.9 ± 12.3 years), and 9 hearing adults (48.9 ± 9.5 years) were preprocessed using FSL software. To find changes in white matter integrity, tract-based spatial statistics was used, which implemented on FSL software. Fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were calculated and compared among the groups with age as a nuisance variable. To find out the effect of onset age or duration of deafness to the white matter integrity, onset-age or duration of deafness was treated as a variable of interest in the general linear model implemented on tract-based spatial statistics. White matter connectivity was constructed by a deterministic tractography and compared among the groups. RESULTS: In comparison to the hearing group, the early-onset deaf group did not show any significant changes but the late-onset deaf group showed decreased FA and increased RD in the several white matter areas. AD in the late-onset deaf group was not significantly different compared with the hearing group. The regions included the corpus callosum, posterior and superior corona radiata, internal capsule, posterior thalamic radiation, superior longitudinal fasciculus, and tapetum of the right hemisphere. Increased RD was also additionally observed in the right external capsule, fornix, and cerebral peduncle. The onset age or duration of deafness was not significantly correlated with the white matter integrity in the early-onset deaf group. In contrast, the onset age showed a significantly positive correlation with the RD, and a negative correlation with the FA, in the late-onset deaf group. The correlated white matter areas were also similar to the findings of comparison with the hearing group. In comparison to the hearing group, the early-onset deaf group did not show altered white matter connectivity, while the late-onset deaf group showed decreased white matter connectivity in between the right lingual and hippocampal areas. CONCLUSIONS: The present results suggest that late-onset deaf adults showed decreased FA and increased RD, and early-onset deaf adults showed no difference compared with the hearing group. In the late-onset deaf adults, onset-age showed a significantly positive correlation with RD and negative correlation with FA. Duration of deafness was not significantly correlated with the changes. Increased RD indicating demyelination occurred in the brain, and the changes were not limited to the auditory cortex but expanded to almost whole brain areas, suggesting significant effect of auditory deprivation on the brain later in life. The altered white matter connectivity in between the right limbic-occipital areas observed in the late-onset deaf group might be caused by altered language functions after auditory deprivation. Future studies are necessary incorporating functional and anatomical aspects of the brain changes in deaf group.

Gait Variability Can Predict the Risk of Cognitive Decline in Cognitively Normal Older People.

BACKGROUND: The aim of this study was to investigate the association of gait speed and gait variability, an index of how much gait parameters, such as step time, fluctuate step-to-step, with risk of cognitive decline in cognitively normal elderly individuals. While high gait variability is emerging as an early indicator of dementing illnesses, there is little research on whether high gait variability predicts cognitive decline in cognitively normal elderly who have no evidence of cognitive impairment. METHODS: In this 4-year prospective cohort study on 91 community-dwelling cognitively normal elderly individuals without cerebral ischemic burden or Parkinsonism, we evaluated gait speed and step time variability using a tri-axial accelerometer placed on the center of body mass, and diagnosed mild cognitive impairment (MCI) according to the International Working Group on MCI. We performed Kaplan-Meier analysis with consecutive log-rank testing for MCI-free survival by cohort-specific tertiles of gait speed; hazard ratios (HR) of incident MCI were estimated using Cox proportional hazards regression analysis adjusted for age, sex, education level, Cumulative Illness Rating Scale score, GDS score, and presence of the apolipoprotein E ε4 allele. RESULTS: Out of the 91 participants in the baseline assessment, 87 completed one or more 2-year follow-up assessments, and the median duration of follow-up was 47.1 months. Kaplan-Meier curves of incident MCI show evident differences in risk by gait variability group (χ2 = 9.64, p = 0.002, log-rank test). Mean MCI-free survival in the high variability group was 12% shorter than in the mid-to-low tertile group (47.4 ± 1.74 [SD] vs. 54.04 ± 0.52 months), while it was comparable between gait speed groups (51.59 ± 0.70 vs. 50.64 ± 1.77 months; χ2 = 1.16, p = 0.281). In multivariate analysis, subjects with high gait variability showed about 12-fold higher risk of MCI (HR = 11.97, 95% CI = 1.29-111.37) than those with mid-to-low variability. However, those with slow gait speed showed comparable MCI risk to those with mid-to-high speed (HR = 5.04, 95% CI = 0.53-48.18). CONCLUSIONS: Gait variability may be a better predictor of cognitive decline than gait speed in cognitively normal elderly individuals without cerebral ischemic burden or Parkinsonism.

Distinct vestibular phenotypes in DFNA9 families with COCH variants.

Mutations of COCH can cause hearing loss and less frequently vestibular symptoms. However, vestibular phenotypes, especially in terms of the location of specific variants are not well documented yet. In this study, a retrospective and prospective cohort survey was performed in two tertiary referral hospitals to demonstrate vestibular phenotypes of DFNA9 subjects with a focus on the relationship with the location of COCH mutations. Two DFNA9 subjects were recruited from the previously collected cohort, each segregating p.G38D and p.C162Y of the COCH gene. Another two DFNA9 families were newly detected by targeted resequencing of known 129 deafness genes (TRS-129). These two families segregated the p.G38D variant of the COCH gene as the causative mutation, making p.G38D the most frequent COCH mutation in our Korean cohorts. Regarding the detailed clinical phenotype of the four DFNA9 families with documented vestibular phenotypes, we were able to classify them into two groups: one (p.C162Y variant) with a Meniere's disease (MD)-like phenotype and the other three (p.G38D variant) with significant bilateral vestibular loss without any definite MD symptoms. Distinct vestibular phenotypes depending on the location of COCH mutations were demonstrated, and this study correlates a genotype of p.G38D in COCH to the phenotype of bilateral total vestibular loss, therefore expanding the vestibular phenotypic spectrum of DFNA9 to range from bilateral vestibular loss without episodic vertigo to MD-like features with devastating episodic vertigo. In addition, the p.G38D variant of the COCH gene is suggested to be a frequent cause of progressive audiovestibular dysfunction in Koreans eventually requiring cochlear implantation.

Auditory brainstem responses to CE-Chirp® stimuli for normal ears and those with sensorineural hearing loss.

OBJECTIVE: Evaluation of the characteristic differences between click-and CE-Chirp-evoked auditory brainstem responses (ABRs) in normal hearing and sensorineural hearing loss. DESIGN: A prospective study. Ears with normal hearing and with sensorineural hearing loss were evaluated. Pure-tone audiometry and click-and CE-Chirp evoked ABRs exams were conducted for all ears. Visual detection levels, wave-V amplitudes, and latencies of the ABRs were assessed. STUDY SAMPLE: Twenty-two ears with normal hearing and 22 ears with sloping type sensorineural hearing loss were examined. RESULTS: In normal-hearing ears, mean amplitudes were larger for CE-chirps than for clicks at all intensities until 80 dB nHL, at which the amplitudes dropped off, presumably due to upward spread of excitation. In ears with sensorineural hearing loss, however the drop-off was less significant at 80 dB nHL. Comparisons with pure-tone audiometry findings revealed ABRs to CE-Chirps to correlate at 0.5, 1, 2, and 3 kHz, and to clicks at 1, 2, 3, and 4 kHz. CONCLUSIONS: The CE-Chirp has advantages over clicks for examining normal ears. However, under high-level stimulation, these advantages are no longer present. In ears with sensorineural hearing loss, the upward spread of excitation is less prominent. The CE-Chirps results correlate significantly to low frequency audiometric findings at 0.5 kHz, while clicks do not.

Large-area assembly of three-dimensional nanoparticle structures via ion assisted aerosol lithography with a multi-pin spark discharge generator.

We present an approach utilizing ion assisted aerosol lithography (IAAL) with a newly designed multi-pin spark discharge generator (SDG) for fabricating large-area three-dimensional (3D) nanoparticle-structure (NPS) arrays. The design of the multi-pin SDG allows us to uniformly construct 3D NPSs on a large area of 50 mm × 50 mm in a parallel fashion at atmospheric pressure. The ion-induced focusing capability of IAAL significantly reduces the feature size of 3D NPSs compared to that of the original pre-patterns formed on a substrate. The spatial uniformity of 3D NPSs is above 95% using the present multi-pin SDG, which is far superior to that of the previous single-pin SDG with less than 32% uniformity. The effect of size distributions of nanoparticles generated via the multi-pin SDG on the 3D NPSs also has been studied. In addition, we measured spectral reflectance for the present 3D NPSs coated with Ag, demonstrating enhanced diffuse reflectance.

Clinical characteristics of persistent postural-perceptual dizziness and its visual subtype in Korean patients: A multicenter cross-sectional study.

OBJECTIVES: Persistent postural-perceptual dizziness (PPPD) is a chronic functional vestibular disorder for which the Bárány Society has established diagnostic criteria. This nationwide multicenter study aims to investigate the clinical features of individuals with definite PPPD and clinical variant PPPD who do not fully meet the diagnostic criteria, with a particular focus on visual exaggeration. METHODS: Between September 2020 and September 2021, a total of 76 individuals with definite PPPD and 109 individuals with clinical variant PPPD who did not meet all three exacerbating factors outlined in Criterion B were recruited from 18 medical centers in South Korea. The study gathered information on demographic factors, clinical manifestations, balance scales, and personality assessments. RESULTS: Comparative analysis between groups with definite PPPD and clinical variant with visual exacerbation revealed no significant differences in sociodemographic characteristics, clinical course, dizziness impact, and specific precipitants. Only disease duration was significantly longer in definite PPPD compared with variant with visual exacerbation. However, the variant without visual exacerbation displayed significantly reduced rates of panic disorder, diminished space-motion discomfort, lesser impact of dizziness, and decreased prevalence of depression when compared with the definitive PPPD. CONCLUSION: This is the first comprehensive nationwide study examining clinical features of both definite PPPD patients and its clinical variants, considering visual exacerbating factors. Differences in dizziness and personality traits emerged between definite PPPD and its potential variant without visual issues. Our results highlight the possibility of a distinct clinical variant of PPPD influenced by visual dependency.

Multiphasic analysis of whole exome sequencing data identifies a novel mutation of ACTG1 in a nonsyndromic hearing loss family.

BACKGROUND: The genetic heterogeneity of sensorineural hearing loss is a major hurdle to the efficient discovery of disease-causing genes. We designed a multiphasic analysis of copy number variation (CNV), linkage, and single nucleotide variation (SNV) of whole exome sequencing (WES) data for the efficient discovery of mutations causing nonsyndromic hearing loss (NSHL). RESULTS: From WES data, we identified five distinct CNV loci from a NSHL family, but they were not co-segregated among patients. Linkage analysis based on SNVs identified six candidate loci (logarithm of odds [LOD] >1.5). We selected 15 SNVs that co-segregated with NSHL in the family, which were located in six linkage candidate loci. Finally, the novel variant p.M305T in ACTG1 (DFNA20/26) was selected as a disease-causing variant. CONCLUSIONS: Here, we present a multiphasic CNV, linkage, and SNV analysis of WES data for the identification of a candidate mutation causing NSHL. Our stepwise, multiphasic approach enabled us to expedite the discovery of disease-causing variants from a large number of patient variants.

Role of microRNA­375­3p­mediated regulation in tinnitus development.

Changes in the dorsal cochlear nucleus (DCN) following exposure to noise play an important role in the development of tinnitus. As the development of several diseases is known to be associated with microRNAs (miRNAs/miRs), the aim of the present study was to identify the miRNAs that may be implicated in pathogenic changes in the DCN, resulting in tinnitus. A previously developed tinnitus animal model was used for this study. The study consisted of four stages, including identification of candidate miRNAs involved in tinnitus development using miRNA microarray analysis, validation of miRNA expression using reverse transcription­quantitative PCR (RT­qPCR), evaluation of the effects of candidate miRNA overexpression on tinnitus development through injection of a candidate miRNA mimic or mimic negative control, and target prediction of candidate miRNAs using mRNA microarray analysis and western blotting. The miRNA microarray and RT­qPCR analyses revealed that miR­375­3p expression was significantly reduced in the tinnitus group compared with that in the non­tinnitus group. Additionally, miR­375­3p overexpression via injection of miR­375­3p mimic reduced the proportion of animals with persistent tinnitus. Based on mRNA microarray and western blot analyses, connective tissue growth factor (CTGF) was identified as a potential target for miR­375­3p. Thus, it was inferred that CTGF downregulation by miR­375­3p may weaken with the decrease in miRNA expression, and the increased pro­apoptotic activity of CTGF may result in more severe neuronal damage, contributing to tinnitus development. These findings are expected to contribute significantly to the development of a novel therapeutic approach to tinnitus, thereby bringing about a significant breakthrough in the treatment of this potentially debilitating condition.

High-resolution, parallel patterning of nanoparticles via an ion-induced focusing mask.

An ion-induced focusing mask under the simultaneous injection of ions and charged aerosols generates invisible electrostatic lenses around each opening, through which charged nanoparticles are convergently guided without depositing on the mask surface. The sizes of the created features become significantly smaller than those of the mask openings due to the focusing capability. It is not only demonstrated that material-independent nanoparticles including proteins can be patterned as an ordered array on any surface regardless of the conductive, nonconductive, or flexible nature of the substrate, but also that the array density can be increased. Highly sensitive gas sensors based on these focused nanoparticle patterns are fabricated via the concept.

Low Diastolic Blood Pressure and Cognitive Decline in Korean Elderly People: The Korean Longitudinal Study on Cognitive Aging and Dementia.

OBJECTIVE: Cardiovascular diseases are representative risk factors for the onset of cognitive decline. The purpose of this study was to confirm the relationship between diastolic blood pressure and cognitive function in elderly people in Korea. METHODS: Data from subjects who were enrolled in the prospective Korean Longitudinal Study on Cognitive Aging and Dementia were used in this study. Data from 701 subjects whose diastolic blood pressure range did not change (≤79 mm Hg or ≥80 mm Hg) over 2 years were analyzed. To analyze the differences in cognitive function between the groups at the 2-year follow-up, an analysis of covariance was performed with covariates, which were significantly different between the two groups, and the baseline cognitive function. RESULTS: Significant differences were observed between the two groups, and the mean scores on the constructional praxis (η2=0.010) and word list recall tests (η2=0.018) in the diastolic blood pressure ≥80 mm Hg group were higher than those in the diastolic blood pressure ≤79 mm Hg group at the 2-year follow-up. CONCLUSION: These results indicate that maintaining a DBP below 79 mm Hg presents a greater risk of cognitive decline in Korean elderly people.

Driving-Related Adverse Events in the Elderly Men: A Population-Based Prospective Cohort Study.

OBJECTIVE: This study estimated the incidence of driving-related adverse events and examined the association of cognitive function with the risk of future driving-related adverse events in the elderly Korean male population. METHODS: We analyzed 1,172 male drivers aged 60 years or older in the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD). Using the data from Korean National Police Agency, we classified the participants into three groups: safe driving (drove for 2 years after baseline without a traffic accident or repeated violations), driving cessation (stopped driving), and risky driving (one or more traffic accidents or repeated violations). We estimated the incidences of driving cessation and risky driving, and examined the effect of cognitive function on their risks. RESULTS: The incidence of driving cessation and risky driving in the Korean male drivers aged 60 years or older was 19.3 and 69.9 per 1,000 person-years respectively and increased in the late 80s. Drivers with better baseline Word List Memory Test scores showed less risky driving (OR=0.94, p=0.039). CONCLUSION: Driving-related adverse events increased in late 80s, and better memory function was protective against these events.

Controlled Enhancement in Hole Injection at Gold-Nanoparticle-on-Organic Electrical Contacts Fabricated by Spark-Discharge Aerosol Technique.

We demonstrate that hole injection from a top electrode composed of Au nanoparticles (AuNPs) capped with a thick Au layer into an underlying organic semiconductor, N, N'-diphenyl- N, N'-bis-[4-(phenyl- m-tolyl-amino)-phenyl]-biphenyl-4,4'-diamine (DNTPD), is significantly enhanced compared to that in a control device whose top electrode is composed entirely of a thick Au layer. The fabrication of this organic hole-only device with the AuNP electrode is made possible by dry, room-temperature distribution of AuNPs onto DNTPD using a spark-discharge aerosol technique capable of varying the average diameter ( D̅) of the AuNPs. The enhancement in hole injection is found to increase with decreasing D̅, with the current density of a device with D̅ = 1.1 nm being more than 3 orders of magnitude larger than that of the control device. Intensity-modulated photocurrent measurements show that the built-in potentials of the devices with the AuNP electrode are smaller than that of the control device by as much as 0.68 V, indicating that the enhanced hole injection originates from the increased work functions of these devices, which in turn decreases the hole injection barrier heights. X-ray photoelectron spectroscopy reveals that the increased work functions of the AuNP electrodes are due to surface oxidation of the AuNPs resulting in AuN and Au3N. The degree of oxidation of the AuNPs increases with decreasing D̅, consistent with the D̅-dependencies of the hole injection enhancement and the built-in potential reduction.

Axonal sprouting in the dorsal cochlear nucleus affects gap­prepulse inhibition following noise exposure.

One of the primary theories of the pathogenesis of tinnitus involves maladaptive auditory­somatosensory plasticity in the dorsal cochlear nucleus (DCN), which is assumed to be due to axonal sprouting. Although a disrupted balance between auditory and somatosensory inputs may occur following hearing damage and may induce tinnitus, examination of this phenomenon employed a model of hearing damage that does not account for the causal relationship between these changes and tinnitus. The present study aimed to investigate changes in auditory­somatosensory innervation and the role that axonal sprouting serves in this process by comparing results between animals with and without tinnitus. Rats were exposed to a noise­inducing temporary threshold shift and were subsequently divided into tinnitus and non­tinnitus groups based on the results of gap prepulse inhibition of the acoustic startle reflex. DCNs were collected from rats divided into three sub­groups according to the number of weeks (1, 2 or 3) following noise exposure, and the protein levels of vesicular glutamate transporter 1 (VGLUT1), which is associated with auditory input to the DCN, and VGLUT2, which is in turn primarily associated with somatosensory inputs, were assessed. In addition, factors related to axonal sprouting, including growth­associated protein 43 (GAP43), postsynaptic density protein 95, synaptophysin, α­thalassemia/mental retardation syndrome X­linked homolog (ATRX), growth differentiation factor 10 (GDF10), and leucine­rich repeat and immunoglobulin domain­containing 1, were measured by western blot analyses. Compared to the non­tinnitus group, the tinnitus group exhibited a significant decrease in VGLUT1 at 1 week and a significant increase in VGLUT2 at 3 weeks post­exposure. In addition, rats in the tinnitus group exhibited significant increases in GAP43 and GDF10 protein expression levels in their DCN at 3 weeks following noise exposure. Results from the present study provided further evidence that changes in the neural input distribution to the DCN may cause tinnitus and that axonal sprouting underlies these alterations.

Losartan Prevents Maladaptive Auditory-Somatosensory Plasticity After Hearing Loss via Transforming Growth Factor-ß Signaling Suppression.

OBJECTIVES: Hearing loss disrupts the balance of auditory-somatosensory inputs in the cochlear nucleus (CN) of the brainstem, which has been suggested to be a mechanism of tinnitus. This disruption results from maladaptive auditory-somatosensory plasticity, which is a form of axonal sprouting. Axonal sprouting is promoted by transforming growth factor (TGF)-ß signaling, which can be inhibited by losartan. We investigated whether losartan prevents maladaptive auditory-somatosensory plasticity after hearing loss. METHODS: The study consisted of two stages: determining the time course of auditory-somatosensory plasticity following hearing loss and preventing auditory-somatosensory plasticity using losartan. In the first stage, rats were randomly divided into two groups: a control group that underwent a sham operation and a deaf group that underwent cochlea ablation on the left side. CNs were harvested 1 and 2 weeks after surgery. In the second stage, rats were randomly divided into either a saline group that underwent cochlear ablation on the left side and received normal saline or a losartan group that underwent cochlear ablation on the left side and received losartan. CNs were harvested 2 weeks after surgery. Hearing was estimated with auditory brainstem responses (ABRs). Western blotting was performed for vesicular glutamate transporter 1 (VGLUT1), reflecting auditory input; vesicular glutamate transporter 2 (VGLUT2), reflecting somatosensory input; growth-associated protein 43 (GAP-43), reflecting axonal sprouting; and p-Smad2/3. RESULTS: Baseline ABR thresholds before surgery ranged from 20 to 35 dB sound pressure level. After cochlear ablation, ABR thresholds were higher than 80 dB. In the first experiment, VGLUT2/VGLUT1 ratios did not differ significantly between the control and deaf groups 1 week after surgery. At 2 weeks after surgery, the deaf group had a significantly higher VGLUT2/VGLUT1 ratio compared to the control group. In the second experiment, the losartan group had a significantly lower VGLUT2/VGLUT1 ratio along with significantly lower p-Smad3 and GAP-43 levels compared to the saline group. CONCLUSION: Losartan might prevent axonal sprouting after hearing loss by blocking TGF-ß signaling thereby preventing maladaptive auditory-somatosensory plasticity.

Normal-But-Low Serum Folate Levels and the Risks for Cognitive Impairment.

OBJECTIVE: This study aimed to examine the association between normal-but-low folate levels and cognitive function in the elderly population using a prospective cohort study. METHODS: We analyzed 3,910 participants whose serum folate levels were within the normal reference range (1.5-16.9 ng/mL) at baseline evaluation in the population-based prospective cohort study named the "Korean Longitudinal Study on Cognitive Aging and Dementia." The association between baseline folate quartile categories and baseline cognitive disorders [mild cognitive impairment (MCI) or dementia] was examined using binary logistic regression analysis adjusting for confounding variables. The risks of incident MCI and dementia associated with the decline of serum folate level during a 4-year follow-up period were examined using multinomial logistic regression analysis. RESULTS: The lowest quartile group of serum folate (≥1.5, ≤5.9 ng/mL) showed a higher risk of cognitive disorders than did the highest quartile group at baseline evaluation (odds ratio 1.314, p=0.012). Over the 4 years of follow-up, the risk of incident dementia was 2.364 times higher among subjects whose serum folate levels declined from the 2nd-4th quartile group to the 1st quartile than among those for whom it did not (p=0.031). CONCLUSION: Normal-but-low serum folate levels were associated with the risk of cognitive disorders in the elderly population, and a decline to normal-but-low serum folate levels was associated with incident dementia. Maintaining serum folate concentration above 5.9 ng/mL may be beneficial for cognitive status.

Overview of the Korean Longitudinal Study on Cognitive Aging and Dementia.

OBJECTIVE: Due to an unprecedented rate of population aging, South Korea is facing a dementia epidemic. For this reason, the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) was launched in 2009 with support from the Korean Health Industry Development Institute to investigate the epidemiology, biopsychosocial risk factors, and outcomes of dementia and dementia-related conditions. METHODS: The KLOSCAD is the first nationwide multi-center population-based prospective cohort study. In October 2010, 12,694 individuals were randomly sampled from residents aged 60 years or older who lived in 13 districts across South Korea. In the baseline assessment, which was conducted from November 2010 through October 2012, 6,818 (53.7%) individuals participated. Follow-up assessments have been conducted every two years, with the first follow-up assessment conducted between November 2012 and October 2014, and the second between November 2014 and October 2016. The third is now in progress, and will span from November 2016 to October 2018. Diagnosis of cognitive disorders, neuropsychological battery, behavioral and psychological symptoms of dementia, activities of daily living, physical and neurologic examination and laboratory tests, life styles, quality of life, and identification of death were evaluated in each assessment. RESULTS: The cumulative drop-out rate at the second follow-up assessment was 38.7%. Dementia and mild cognitive impairment were 5.0% and 27.0%, respectively. CONCLUSION: The KLOSCAD may provide strong scientific evidence for advancing the fight against dementia both in Korea and globally.

Effects of lifetime cumulative ginseng intake on cognitive function in late life.

BACKGROUND: We investigated the effects of lifetime cumulative ginseng intake on cognitive function in a community-dwelling population-based prospective cohort of Korean elders. METHODS: Community-dwelling elders (N = 6422; mean age = 70.2 ± 6.9 years, education = 8.0 ± 5.3 years, female = 56.8%) from the Korean Longitudinal Study on Cognitive Aging and Dementia were included. Among them, 3918 participants (61.0%) completed the 2-year and 4-year follow-up evaluations. Subjects were categorized according to cumulative ginseng intake at baseline evaluation; no use group, low use (< 5 years) group, and high use (≥ 5 years) group. One-way analysis of covariance (ANCOVA) was conducted to compare the impact of cumulative ginseng intake on baseline Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet neuropsychological battery total score (CERAD total score) and Mini-Mental State Examination (MMSE) score among the three groups while adjusting for potential covariates. A repeated-measures ANCOVA was performed to investigate the impacts on the changes in CERAD total scores and MMSE scores during the 4 years of follow-up. RESULTS: The high use group showed higher CERAD total scores compared to the no use group after controlling for age, sex, education years, socioeconomic status, smoking, alcohol intake, presence of hypertension, stroke history, Geriatric Depression Scale, Cumulative Illness Rating Scale, and presence of the APOE e4 allele (F(2, 4762) = 3.978, p = 0.019). The changes of CERAD total score for 2 or 4 years of follow-up did not differ according to the use of ginseng. CONCLUSIONS: Cumulative ginseng use for longer than 5 years may be beneficial to cognitive function in late life.

ATP1A3 mutations can cause progressive auditory neuropathy: a new gene of auditory synaptopathy.

The etiologies and prevalence of sporadic, postlingual-onset, progressive auditory neuropathy spectrum disorder (ANSD) have rarely been documented. Thus, we aimed to evaluate the prevalence and molecular etiologies of these cases. Three out of 106 sporadic progressive hearing losses turned out to manifest ANSD. Through whole exome sequencing and subsequent bioinformatics analysis, two out of the three were found to share a de novo variant, p.E818K of ATP1A3, which had been reported to cause exclusively CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome. However, hearing loss induced by CAPOS has never been characterized to date. Interestingly, the first proband did not manifest any features of CAPOS, except subclinical areflexia; however, the phenotypes of second proband was compatible with that of CAPOS, making this the first reported CAPOS allele in Koreans. This ANSD phenotype was compatible with known expression of ATP1A3 mainly in the synapse between afferent nerve and inner hair cells. Based on this, cochlear implantation (CI) was performed in the first proband, leading to remarkable benefits. Collectively, the de novo ATP1A3 variant can cause postlingual-onset auditory synaptopathy, making this gene a significant contributor to sporadic progressive ANSD and a biomarker ensuring favorable short-term CI outcomes.

Establishment of a Flexible Real-Time Polymerase Chain Reaction-Based Platform for Detecting Prevalent Deafness Mutations Associated with Variable Degree of Sensorineural Hearing Loss in Koreans.

Many cutting-edge technologies based on next-generation sequencing (NGS) have been employed to identify candidate variants responsible for sensorineural hearing loss (SNHL). However, these methods have limitations preventing their wide clinical use for primary screening, in that they remain costly and it is not always suitable to analyze massive amounts of data. Several different DNA chips have been developed for screening prevalent mutations at a lower cost. However, most of these platforms do not offer the flexibility to add or remove target mutations, thereby limiting their wider use in a field that requires frequent updates. Therefore, we aimed to establish a simpler and more flexible molecular diagnostic platform based on ethnicity-specific mutation spectrums of SNHL, which would enable bypassing unnecessary filtering steps in a substantial portion of cases. In addition, we expanded the screening platform to cover varying degrees of SNHL. With this aim, we selected 11 variants of 5 genes (GJB2, SLC26A4, MTRNR1, TMPRSS3, and CDH23) showing high prevalence with varying degrees in Koreans and developed the U-TOP™ HL Genotyping Kit, a real-time PCR-based method using the MeltingArray technique and peptide nucleic acid probes. The results of 271 DNA samples with wild type sequences or mutations in homo- or heterozygote form were compared between the U-TOP™ HL Genotyping Kit and Sanger sequencing. The positive and negative predictive values were 100%, and this method showed perfect agreement with Sanger sequencing, with a Kappa value of 1.00. The U-TOP™ HL Genotyping Kit showed excellent performance in detecting varying degrees and phenotypes of SNHL mutations in both homozygote and heterozygote forms, which are highly prevalent in the Korean population. This platform will serve as a useful and cost-effective first-line screening tool for varying degrees of genetic SNHL and facilitate genome-based personalized hearing rehabilitation for the Korean population.

Usefulness of 1000-Hz probe tone in tympanometry according to age in Korean infants.

OBJECTIVE: Numerous studies have shown the superiority of a 1000-Hz frequency probe tone for evaluating the middle ear status of infants. However, most of these studies examined Caucasian populations. This study validated the 1000-Hz probe tone and evaluated the age at which it should be used in Korean infants. METHODS: Data from 83 infants (43 males, 40 females; mean age 9.2±6.2 (range 1-30) months, 165 ears) were analyzed. Tympanograms were classified according to Baldwin's modification of the method of Marchant et al. and correlated with results based on combined diagnostic tests, including an endoscopic examination of the tympanic membrane, myringotomy findings, and the air and bone conduction auditory brainstem response (ABR) thresholds. Data were analyzed in five age groups, each covering a 3-month range. The traces were measured for both 226- and 1000-Hz probe tones. The sensitivity and specificity for the different age groups were also determined. RESULTS: For the 226-Hz probe tone, the tympanograms showed normal traces for most ears with otitis media effusions in infants younger than 12 months. By contrast, the tympanograms using the 1000-Hz probe tone showed abnormal traces in most of the infants with otitis media effusions in all age groups. In infants with no otitis media effusion, the tympanograms using both 226- and 1000-Hz probe tones were interpreted as normal in most cases in all age groups. In infants younger than 12 months, the sensitivity of the 226-Hz probe tone was very low (0-6.6%), whereas that of the 1000-Hz probe tone was very high (90-100%). In infants older than 13 months, however, the sensitivities of the 226- and 1000-Hz probe tones were 76.2% and 85.7%, respectively. Regarding specificity, the difference between the two probe tones was not significant for any age group. CONCLUSIONS: This study confirmed the superiority of the 1000-Hz probe tone for evaluating the middle ear in infants. We recommend using a 1000-Hz probe tone at least up to the age of 12 months for Korean infants.