The Rotterdam Study. Design update and major findings between 2020 and 2024

European Journal of Epidemiology, Год журнала: 2024, Номер 39(2), С. 183 - 206

Опубликована: Фев. 1, 2024

Язык: Английский

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Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice

Science Translational Medicine, Год журнала: 2023, Номер 15(702)

Опубликована: Июнь 28, 2023

Inner ear gene therapy has recently effectively restored hearing in neonatal mice, but it is complicated adulthood by the structural inaccessibility of cochlea, which embedded within temporal bone. Alternative delivery routes may advance auditory research and also prove useful when translated to humans with progressive genetic-mediated loss. Cerebrospinal fluid flow via glymphatic system emerging as a new approach for brain-wide drug rodents well humans. The cerebrospinal inner are connected bony channel called cochlear aqueduct, previous studies have not explored possibility delivering restore adult deaf mice. Here, we showed that aqueduct mice exhibits lymphatic-like characteristics. In vivo time-lapse magnetic resonance imaging, computed tomography, optical fluorescence microscopy large-particle tracers injected into reached dispersive transport A single intracisternal injection adeno-associated virus carrying solute carrier family 17, member 8 ( Slc17A8 ), encodes vesicular glutamate transporter-3 (VGLUT3), rescued −/− restoring VGLUT3 protein expression hair cells, minimal ectopic brain none liver. Our findings demonstrate comprises an accessible route represent important step toward using

Язык: Английский

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The Stria Vascularis in Mice and Humans Is an Early Site of Age-Related Cochlear Degeneration, Macrophage Dysfunction, and Inflammation

Journal of Neuroscience, Год журнала: 2023, Номер 43(27), С. 5057 - 5075

Опубликована: Июнь 2, 2023

Age-related hearing loss, or presbyacusis, is a common degenerative disorder affecting communication and quality of life for millions older adults. Multiple pathophysiologic manifestations, along with many cellular molecular alterations, have been linked to presbyacusis; however, the initial events causal factors not clearly established. Comparisons transcriptome in lateral wall (LW) other cochlear regions mouse model (of both sexes) “normal” age-related loss revealed that early pathophysiological alterations stria vascularis (SV) are associated increased macrophage activation signature indicative inflammaging, form immune dysfunction. Structure-function correlation analyses mice across lifespan showed age-dependent increase decline auditory sensitivity. High-resolution imaging analysis middle-aged aged human cochleas, transcriptomic changes gene expression, support hypothesis aberrant activity an important contributor strial dysfunction, pathology, loss. Thus, this study highlights SV as primary site degeneration dysregulation system indicators pathology Importantly, novel new methods described here now provide means analyze temporal bones way had previously feasible thereby represent significant tool otopathological evaluation. SIGNIFICANCE STATEMENT neurodegenerative life. Current interventions (primarily aids implants) offer imperfect often unsuccessful therapeutic outcomes. Identification crucial development treatments diagnostic tests. Here, we find SV, nonsensory component cochlea, structural functional humans characterized by cell activity. We also establish technique evaluating cochleas from bones, but understudied area research because lack well-preserved specimens difficult tissue preparation processing approaches.

Язык: Английский

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Genetic architecture distinguishes tinnitus from hearing loss

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 19, 2024

Abstract Tinnitus is a heritable, highly prevalent auditory disorder treated by multiple medical specialties. Previous GWAS indicated high genetic correlations between tinnitus and hearing loss, with little indication of differentiating signals. We present meta-analysis, triple previous sample sizes, expand to non-European ancestries. in 596,905 Million Veteran Program subjects identified 39 loci, genes related neuronal synapses cochlear structural support. Applying state-of-the-art analytic tools, we confirm large number shared variants, but also distinct architecture tinnitus, higher polygenicity proportion variants not difficulty. Tissue-expression analysis for infers broad enrichment across most brain tissues, contrast Finally, only correlated spectrum psychiatric disorders, providing potential new avenues treatment. This study establishes as separate from difficulties.

Язык: Английский

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Mendelian non-syndromic and syndromic hearing loss genes contribute to presbycusis

European Journal of Human Genetics, Год журнала: 2025, Номер unknown

Опубликована: Март 7, 2025

Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants well-established Mendelian HL genes play an important role ARHL etiology. In all identified 32 which are associated with ARHL. We performed single and rare-variant aggregate association analyses using exome data obtained from white-Europeans self-reported phenotypes UK Biobank. Our analysis revealed previously unreported associations between non-syndromic syndromic genes, including MYO15A, WFS1. Additionally, i.e., ACTG1, GRHL2, KCNQ4, MYO7A, PLS1, TMPRSS3, TNRC6B. Four novel were also detected: FBXO2 PALM3, implicated mice, TWF1, Dalmatian dogs, TXNDC17. In-silico provided further evidence of inner ear expression these both murine human models, supporting their relevance to Analysis variants minor allele frequency >0.005 additional known e.g., ILDR1 ABHD12, COA8, KANSL1, SERAC1, UBE3B as well have not been reported be involved VCL. Rare-variants typically exhibited higher effect sizes for compared those other genes. conclusion, this study highlights critical etiology

Язык: Английский

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Variability in Cochlear Implantation Outcomes in a Large German Cohort With a Genetic Etiology of Hearing Loss

Ear and Hearing, Год журнала: 2023, Номер 44(6), С. 1464 - 1484

Опубликована: Июль 13, 2023

The variability in outcomes of cochlear implantation is largely unexplained, and clinical factors are not sufficient for predicting performance. Genetic have been suggested to impact outcomes, but the genetic heterogeneity hereditary hearing loss makes it difficult determine interpret postoperative It hypothesized that mutations affect neuronal components cochlea auditory pathway, targeted by implant (CI), may lead poor A large cohort CI recipients was studied verify this hypothesis.This study included a German (n = 123 implanted ears; n 76 probands) with definitive etiology according American College Medical Genetics (ACMG)/Association Molecular Pathology (AMP) guidelines documented audiological outcomes. All patients underwent preoperative examinations. Postoperative outcome measures were based on at least 1 year follow-up postlingual onset (>6 years) 5 years children congenital or pre/perilingual (≤6 years). analysis performed three different methods single-gene screening, custom-designed gene panel sequencing, targeting known syndromic nonsyndromic genes, whole-genome sequencing.The diagnosis probands involved 35 genes 61 clinically relevant (pathogenic, likely pathogenic) variants. With regard ears 123), six most frequently affected affecting nearly one-half GJB2 (21%; 26), TMPRSS3 (7%; 9), MYO15A 8), SLC26A4 (5%; 6), LOXHD1 USH2A (each 4%; 5). pathogenic variants influence sensory nonneural structures above median level speech performance all 70% [monosyllable word recognition score quiet 65 decibels sound pressure (SPL)]. When expression categories compared demographic (total number categories: 30), expressed spiral ganglion emerged as significant factor more negatively than parameters. An ANOVA reduced set 10) identified five detrimental leading poorer highly effects ( p < 0.001), accounting total 11.8% observed variance. single strongest category neural 3.1% variance.The relationship between molecular diagnoses revealed variabilities. Poor cochlea, supporting "spiral hypothesis."

Язык: Английский

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Clarin-2 gene supplementation durably preserves hearing in a model of progressive hearing loss

Molecular Therapy, Год журнала: 2024, Номер 32(3), С. 800 - 817

Опубликована: Янв. 18, 2024

Hearing loss is a major health concern affecting millions of people worldwide with currently limited treatment options. In clarin-2-deficient Clrn2

Язык: Английский

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Rare-variant association analysis reveals known and new age-related hearing loss genes

European Journal of Human Genetics, Год журнала: 2023, Номер 31(6), С. 638 - 647

Опубликована: Фев. 15, 2023

Язык: Английский

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The actin cytoskeleton in hair bundle development and hearing loss

Hearing Research, Год журнала: 2023, Номер 436, С. 108817 - 108817

Опубликована: Май 26, 2023

Язык: Английский

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The Stria Vascularis: Renewed Attention on a Key Player in Age-Related Hearing Loss

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(10), С. 5391 - 5391

Опубликована: Май 15, 2024

Age-related hearing loss (HL), or presbycusis, is a complex and heterogeneous condition, affecting significant portion of older adults involving various interacting mechanisms. Metabolic type age-related HL, characterized by the dysfunction stria vascularis, which crucial for maintaining endocochlear potential necessary hearing. Although attention on metabolic presbycusis has waned in recent years, research continues to identify strial pathology as key factor HL. This narrative review integrates past research, bridging findings from animal models human studies, examine contributions vascularis It provides brief overview structure function then examines mechanisms contributing dysfunction, including altered ion transport, changes pigmentation, inflammatory responses, vascular atrophy. Importantly, this outlines contribution highlighting areas future research. emphasizes interdependence sensorineural HL highlights importance understanding underlying The comprehensive mechanistic investigation all factors cochlear remains identifying developing personalized, protective, restorative treatments.

Язык: Английский

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