Cholinergic Hypofunction in Presbycusis-Related Tinnitus With Cognitive Function Impairment: Emerging Hypotheses

Abstract

Presbycusis (age-related hearing loss) is a potential risk factor for tinnitus and cognitive deterioration, which result in poor life quality. Presbycusis-related tinnitus with cognitive impairment is a common phenotype in the elderly population. In these individuals, the central auditory system shows similar pathophysiological alterations as those observed in Alzheimer’s disease (AD), including cholinergic hypofunction, epileptiform-like network synchronization, chronic inflammation, and reduced GABAergic inhibition and neural plasticity. Observations from experimental rodent models indicate that recovery of cholinergic function can improve memory and other cognitive functions via acetylcholine-mediated GABAergic inhibition enhancement, nicotinic acetylcholine receptor (nAChR)-mediated anti-inflammation, glial activation inhibition and neurovascular protection. The loss of cholinergic innervation of various brain structures may provide a common link between tinnitus seen in presbycusis-related tinnitus and age-related cognitive impairment. We hypothesize a key component of the condition is the withdrawal of cholinergic input to a subtype of GABAergic inhibitory interneuron, neuropeptide Y (NPY) neurogliaform cells. Cholinergic denervation might not only cause the degeneration of NPY neurogliaform cells, but may also result in decreased AChR activation in GABAergic inhibitory interneurons. This, in turn, would lead to reduced GABA release and inhibitory regulation of neural networks. Reduced nAChR-mediated anti-inflammation due to the loss of nicotinic innervation might lead to the transformation of glial cells and release of inflammatory mediators, lowering the buffering of extracellular potassium and glutamate metabolism. Further research will provide evidence for the recovery of cholinergic function with the use of cholinergic input enhancement alone or in combination with other rehabilitative interventions to reestablish inhibitory regulation mechanisms of involved neural networks for presbycusis-related tinnitus with cognitive impairment.

Heterogeneous Influence of Frailty Phenotypes in Age-Related Hearing Loss and Tinnitus in Chinese Older Adults: An Explorative Study

“…Although HL is associated with cognitive impairment, frailty, and motor dysfunction ( Chen et al, 2014 ; Panza et al, 2015 ; Kamil et al, 2016 ; Deal et al, 2017 ; Bang et al, 2020 ; Bonfiglio et al, 2020 ), identifying the causal relationship between HL and frailty phenotype and cognition decline is difficult because HL is similar to pre-MCI, with long subclinical period ( Golub et al, 2019 , 2020 ). Our results revealed that aging does not increase the severity of tinnitus and confirmed the reports of previous studies, which indicated that depression increases the risk for severe HL or tinnitus ( Shargorodsky et al, 2010 ; Langguth et al, 2013 ; House et al, 2018 ; Ruan et al, 2018 ; Jafari et al, 2019 ; Golub et al, 2020 ). Hypertension was a risk factor for tinnitus ( Shargorodsky et al, 2010 ).…”

“…Apart from frailty phenotypes, age was the most significant independent risk factor for HL severity and HL with tinnitus. Previous epidemiological studies revealed that the prevalence of sensory and motor dysfunction and cognition deficit, frailty, and tinnitus increases with age ( Shargorodsky et al, 2010 ; Panza et al, 2015 ; Ruan et al, 2018 ; Jafari et al, 2019 ). Although HL is associated with cognitive impairment, frailty, and motor dysfunction ( Chen et al, 2014 ; Panza et al, 2015 ; Kamil et al, 2016 ; Deal et al, 2017 ; Bang et al, 2020 ; Bonfiglio et al, 2020 ), identifying the causal relationship between HL and frailty phenotype and cognition decline is difficult because HL is similar to pre-MCI, with long subclinical period ( Golub et al, 2019 , 2020 ).…”

“…Individuals with HL had memory ( Deal et al, 2017 ) and executive dysfunctions ( Lin et al, 2013 ). The cognitive deficits of patients with tinnitus included executive domain, working memory, processing speeds, and attention ( Ruan et al, 2018 ; Jafari et al, 2019 ). Our study further confirmed that the differences in HL and tinnitus severity and the presentation of HL and/or tinnitus are independently associated with the z-scores of memory (recognition), attention, and executive function (TMT A and TMT B), as well as language (BNT and animal fluency).…”

“…Subjective tinnitus is another common comorbid disorder of the auditory system in older adults. Apart from an aberrant auditory sensory perception, chronic tinnitus is closely associated with cognitive deficits and emotional, psychological, and mental health disorders, such as depression, anxiety, and sleep disturbance or insomnia ( Langguth et al, 2013 ; Ruan et al, 2018 ; Jafari et al, 2019 ). Chronic tinnitus-related cognitive impairment includes working memory, executive control of attention, and processing speeds.…”

Presbycusis-Related Tinnitus and Cognitive Impairment: Gender Differences and Common Mechanisms

“…Presbycusis and dementia may share some common pathophysiological mechanisms [50,51] once degradation on one pathway may accelerate the degradation on each other disease. The hypothetical mechanistic pathways are still uncertain.…”