Purpose

Hearing loss (HL) is one of the most common age-related diseases. Here, we investigate the central auditory correlates of HL in people with normal cognition and mild cognitive impairment (MCI) and test their association with genetic markers with the aim of revealing pathogenic mechanisms.

Methods

Brain glucose metabolism based on FDG-PET, self-reported HL status, and genetic data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. FDG-PET data was analysed from 742 control subjects (non-HL with normal cognition or MCI) and 162 cases (HL with normal cognition or MCI) with age ranges of 72.2 ± 7.1 and 77.4 ± 6.4, respectively. Voxel-wise statistics of FDG uptake differences between cases and controls were computed using the generalised linear model in SPM12. An additional 1515 FDG-PET scans of 618 participants were analysed using linear mixed effect models to assess longitudinal HL effects. Furthermore, a quantitative trait genome-wide association study (GWAS) was conducted on the glucose uptake within regions of interest (ROIs), which were defined by the voxel-wise comparison, using genotyping data with 5,082,878 variants available for HL cases and HL controls (N = 817).

Results

The HL group exhibited hypometabolism in the bilateral Heschl’s gyrus (k_left = 323; k_right = 151; T_left = 4.55; T_right = 4.14; peak P_uncorr < 0.001), the inferior colliculus (k = 219;T = 3.53; peak P_uncorr < 0.001) and cochlear nucleus (k = 18;T = 3.55; peak P_uncorr < 0.001) after age correction and using a cluster forming height threshold P < 0.005 (FWE-uncorrected). Moreover, in an age-matched subset, the cluster comprising the left Heschl’s gyrus survived the FWE-correction (k_left = 1903; T_left = 4.39; cluster P_FWE-corr = 0.001). The quantitative trait GWAS identified no genome-wide significant locus in the three HL ROIs. However, various loci were associated at the suggestive threshold (p < 1e-05).

Conclusion

Compared to the non-HL group, glucose metabolism in the HL group was lower in the auditory cortex, the inferior colliculus, and the cochlear nucleus although the effect sizes were small. The GWAS identified candidate genes that might influence FDG uptake in these regions. However, the specific biological pathway(s) underlying the role of these genes in FDG-hypometabolism in the auditory pathway requires further investigation.

中文翻译：

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ADNI 队列中年龄相关性听力损失患者听觉通路中的葡萄糖代谢低下

目的

听力损失（HL）是最常见的与年龄相关的疾病之一。在这里，我们研究了认知正常和轻度认知障碍 (MCI) 人群中 HL 的中枢听觉相关性，并测试它们与遗传标记的关联，旨在揭示致病机制。

方法

基于 FDG-PET 的脑葡萄糖代谢、自我报告的 HL 状态以及从阿尔茨海默病神经影像倡议 (ADNI) 队列中获得的遗传数据。FDG-PET 数据分析来自 742 名对照受试者（具有正常认知或 MCI 的非 HL）和 162 名年龄范围分别为 72.2 ± 7.1 和 77.4 ± 6.4 的病例（具有正常认知或 MCI 的 HL）。使用 SPM12 中的广义线性模型计算病例和对照之间 FDG 摄取差异的体素统计数据。使用线性混合效应模型对 618 名参与者的另外 1515 次 FDG-PET 扫描进行了分析，以评估纵向 HL 效应。此外，还对感兴趣区域 (ROI) 内的葡萄糖摄取进行了数量性状全基因组关联研究 (GWAS)，该研究是通过体素比较来定义的，使用的基因分型数据包含 HL 病例和 HL 对照的 5,082,878 个变异体（N = 817）。

结果

HL组在双侧Heschl回（k_左 = 323; k_右 = 151; T_左 = 4.55; T_右 = 4.14;峰值P _uncorr  < 0.001）、下丘（k = 219; T = 3.53; T = 4.55; T右= 4.14;峰值P uncorr < 0.001）表现出代谢低下。 年龄校正后并使用簇形成高度阈值 P < 0.005（FWE 未校正）后，峰值 P uncorr < 0.001）和_耳蜗 核（k = 18；T = 3.55；峰值 P uncorr < 0.001 _{） 。}此外，在年龄匹配的子集中，包含左侧 Heschl 回的簇在 FWE 校正后幸存下来（k _left  = 1903；T _left  = 4.39；簇 P _FWE-corr  = 0.001）。数量性状 GWAS 在三个 HL ROI 中未发现全基因组显着位点。然而，多个基因座在提示阈值处相关（p < 1e-05）。

结论

与非 HL 组相比，HL 组听觉皮层、下丘和耳蜗核的葡萄糖代谢较低，尽管效应较小。GWAS 确定了可能影响这些区域 FDG 吸收的候选基因。然而，这些基因在听觉通路 FDG 代谢减退中作用的具体生物学途径需要进一步研究。