Introduction

Presbycusis (PC) is characterized by bilateral symmetric progressive neurological hearing loss¹. Numerous studies have demonstrated that presbycusis is closely related to cognitive impairment^2,3,4. However, the pathological and physiological mechanisms of presbycusis and its association with cognitive impairment are still poorly understood. Previous magnetic resonance imaging (MRI) studies have suggested cognitive impairment in presbycusis patients is related to the auditory cortex and cognitive-related cortex^5,6,7. A study using PCASL observed significantly reduced CBF levels in the right primary auditory cortex of patients with presbycusis, which were associated with hearing loss⁸. However, the study did not continue to explore whether CBF values in other brain regions decreased, nor did it investigate the relationship between CBF decline and cognitive impairment. A study using MEGA-PRESS found decreased auditory GABA levels in presbycusis patients, which was closely associated with hearing loss⁹. Another MEGA-PRESS study found that decreased GABA levels were related to decreased executive function in patients with presbycusis¹⁰. Notably, a study of healthy subjects found a positive correlation between baseline GABA and cerebral blood flow (CBF) in the visual cortex¹¹. Thus, aberrant GABA and Glu levels in presbycusis patients measured by MRS are likely related to alterations in CBF. In summary, we hypothesized that abnormal metabolite levels and neurotransmitter concentrations are associated with cognitive impairment, and studied the auditory GABA and Glu levels, CBF and their relationship with auditory and cognitive function in presbycusis patients and healthy controls.

Methods

One hundred and twenty-four patients with presbycusis and ninety-one normal hearing (NH) controls were recruited for this research. We evaluated their hearing levels at the 0.5, 1, 2, and 4 kHz thresholds using the pure tone average (PTA) method¹⁰. To assess auditory information processing speed and executive function, the Trail-Making Test(TMT) Part A(TMT-A) and Part B(TMT-B)¹² were administered¹³ . CBF data was gathered by PCASL. GABA-edited data was gathered through a macromolecules (MM)-suppressed MEGA-PRESS sequence utilizing a symmetrical-suppression method to suppress the MM signal^10,13., and the PRESS sequence was used to collect the Glu data.

Results

No statistically significant difference was found in fitting error or CRLB between groups within the bilateral auditory regions (all p > 0.05, Table 1). Compared with the NH group, presbycusis patients had decreased GABA levels in bilateral auditory region (left: 1.10 ± 0.22 i.u. vs 0.98 ± 0.32 i.u., p < 0.001, right: 1.36 ± 0.30 i.u. vs 1.17 ± 0.27 i.u., p < 0.001). Furthermore, decreased Glu levels were found in bilateral auditory regions in patients with presbycusis (left: 4.71 ± 0.69 i.u. vs. 4.39 ± 0.71 i.u., p = 0.001, right: 4.54 ± 0.62 vs 4.19 ± 0.99 i.u., p = 0.002, Table 1).
Compared with NH group, CBF in bilateral insula, precuneus, central operculum and medial frontal gyrus of presbycusis patients decreased significantly. At the same time, CBF was also significantly decreased in the right auditory cortex, anterior cingulate gyrus, superior occipital gyrus, inferior parietal lobule, calcarine fissure and surrounding cortex, angular gyrus, and left caudate nucleus, thalamus, superior frontal gyrus, superior parietal gyrus, middle cingulate cortex ( FDR correction, p < 0.05; clustering defined threshold, P = 0.001), as shown in Table 2 and Fig. 1.
The serial mediation model revealed a significant total effect (c = 0.6528, p = 0.0162), suggesting that PTA predicts TMT-A scores in presbycusis patients (Fig. 2). In the path analysis, PTA was negatively related to GABA levels in the right auditory region (a1 = 0.0092, p = 0.0001) and negatively related to SPG CBF (a2 = -0.0785, p = 0.3441). The right auditory GABA levels were positively related to AN-DMN FC (a3 = 8.3799, p = 0.0094) and negatively related to TMT-A scores (b1 = -43.505, p = 0.0001). The SPG CBF was negatively related to TMT-A scores (b2 = 0.9134, p = 0.0025). After controlling for GABA levels and SPG CBF, the direct effect of PTA on TMT-A scores was no longer statistically significant (c’ = 0.2504，p=0.3483). The total indirect effect was significant (a1×b1+ a2×b2 + a1×a3×b2 = 0.4024, 95%CI[0.0816，0.7652]), with a significant serial indirect effect observed from PTA via GABA levels and SPG CBF to TMT-A scores (a1×a3×b2 = 0.0706, 95%CI[-0.1818，-0.0133]).

Conclusion

This study shows that hearing loss in presbycusis patients can lead to decreased auditory GABA, Glu levels and CBF levels, and this phenomenon is related to decreased speech perception or cognitive impairment. Importantly, decreased auditory GABA levels and decreased CBF levels mediate the association between hearing loss and impaired information processing speed in presbycusis patients.

Acknowledgements

Over the course of my researching and writing this paper, I would like to express my thanks to all those who have helped me. A special acknowledgement should be shown to Doctor Yao Wang and Doctor Fei Gao, who gave me kind encouragement and useful instruction all through my writing. Sincere gratitude should also go to all my partners, friends and family who have greatly helped me in my study as well as in my life.

References

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