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1 --Metabolic presbycusis (discrimination 100%)

2---Cochlear presbycusis (discrimination 96%)

3 Sensory presbycusis (discrimination 98%)

(E) 4 ■ Neura pi'esbyc..isis {discrimiTaiion 60,J.:;

FIGURE 8 (A) Schematic cross section of human cochlea; (B-E) typical pure-tone audiograms of aged individuals suffering from different types of presbycusis (sensory, neural, cochlear, conductive, and strial). Each type of presbycusis reflects damage to a different component of the peripheral auditory system: sensory, to hair cells; neural, to primary auditory neurons; cochlear, to basilar membrane; and strial, to cells of the stria vascularis. Source: From Ref. 123.

hearing loss of unknown cause, revealed changes to the ultrastructure of the stereocilia, pillar cells, stria vascularis, spiral ligament, and the cuticular plate, the latter showing the greatest structural degradation (138). Thus, cuticular plate deformation may play a role in hearing loss, although so far, this has only been proven in guinea pigs (139). How age relates to otopathic function of the inner ear is still undetermined.

Spiral Ganglion and Other Neural Pathways

A quantitative study by Felder et al. (140) of neuron and fiber number in the auditory pathways of aged individuals with presbycusis showed clear evidence of cell and fiber loss, with more loss in peripheral structures than in central ones; normal controls showed no significant loss. Retrograde degeneration from the periphery to the spiral ganglion may be happening in presbycusis. Because interneuronal connections occur in human spiral ganglions, a trophic supply from other neurons at the spiral ganglion level may slow central axon degeneration in these cases. (See Box 8 for effects of neurotrophins.)

Aging Changes in the Cochlear Nucleus

In a recent review of experimental animal studies on age-related structural and functional changes in the cochlear nucleus, Frisina and Walton (141) concluded that cochlear (i.e., peripheral) age-related hearing loss (ARHL) changes are the primary inducing force of age-related alterations in cochlear nucleus. Also age-related auditory perceptual deficiencies such as a decline in complex auditory processing (isolating individual voice in room of people) may be related to the following physiological changes in the cochlear nucleus: (i) alterations in synaptic processing; (ii) a decline in the inhibitory effects of the neurotransmitter glycine with age; (iii) disruptions of temporal processing of information (141).

Possible Hormonal Effects on Presbycusis

Other physiological changes affecting presbycusis may include hormones such as aldosterone, which is known to influence salt transport in the kidney. In a recent study, Tadros et al. (142) found that elderly humans with presbycusis also had significantly lower aldosterone levels, suggesting that normal or high aldosterone level may be protective against presbycusis. Aldosterone may exert this effect by controlling K+ and Cl~ transport in the cochlea by regulating the expression of their transporters as well as that of Na+-K+-ATPase. The authors note that the intracellular pathway of K+ recycling in the human cochlea from the organ of Corti back to the stria vascularis is essential for maintaining viable hearing. Also type II, type IV, and type V fibroblasts are central to this recycling and are located in the stria vascularis, among other cochlear locations such as the nerve endings of the inner and outer hair cells.

■ Treatment of ARHL

Conventional Hearing Aids vs. Cochlear Implants

Currently, a satisfactory plan for rehabilitation and fitting of hearing aids does not exist. Further research and efforts are needed to develop better hearing aids that satisfy more precisely the needs of the elderly (143). Older adults and their immediate family can benefit from information and advice about the serious consequences of presbycusis.

For older patients, hearing aids remove many of the sensory, speech, perceptual, and psychological handicaps of hearing impairment (Boxes 5 and 6). Few older adults with hearing loss actually use hearing aids. Intervention and screening programs need to be improved to better identify older adults in need of amplification, whose quality of life would be improved with such treatment (144). Nursing-home patients have been found to consistently use their hearing aids. Amplification alone, however, does not serve all of the communication needs of the nursing-home residents. Environmental modification as well as improved assistive listening devices (Boxes 5 and 6 as well as Chapter 25) would increase quality of life and the ability to communicate for these patients (145).

BOX 5 Cochlear Implants

These novel neural prosthetic devices involve direct electrical stimulation of the auditory nerve, bypassing the sensory hair cells altogether. Through cochlear implants, elderly patients who are deaf can hear sound and understand speech, thereby improving their quality-of-life significantly (146,147). A holistic method has been developed to determine the appropriate treatment to improve hearing in people with varying degrees of audiological deficits, based on their communicative, physical, social and psychological profiles; a diagnostic flowchart is used to best match high-tech devices with appropriate candidates (148).

Cochlear implants are used to restore hearing in people with profound deafness; these neural prosthetic devices were designed initially for aging people but are increasingly used in all age groups. Bypassing the inner ear, cochlear implants directly stimulate the auditory nerve, through tiny wires inserted into the cochlea. Sounds are received by an external microphone placed behind the ear and are processed by a pocket speech processor, which converts sounds to electrical impulses, which are then transmitted (via FM signals) by a coil placed behind the ear, to an implanted receiver/stimulator. This receiver stimulates the appropriate electrodes, which in turn stimulate multiple populations of auditory nerve fibers, as in the case of multichannel cochlear implants. Multichannel stimulation allows for pitch perception, important for speech recognition. A typical 22-channel cochlear implant transmits in theory up to 22 unique pitch signals to the inner ear, but in practice only six to eight channels are usable concurrently. To improve the performances of the cochlear implants further, it is essential to increase the number of usable channels. Various approaches are being tried, including novel engineering designs, as well as designing "biomolecular cochlear implants," toward achieving this goal (145,146,148-149).

BOX 6 Next Generation of Hearing Aids for Improving Speech Recognition

Speech recognition is difficult for the elderly in the presence of background sounds. As described previously, conventional hearing aids offer little help in this regard. A new system being developed by Professor Albert Feng and collaborators at the Beckman Institute of the University of Illinois, Urbana-Champaign, using biaural microphones and sophisticated digital devices, offers to enhance speech recognition by removing multiple competing noise in the background (150).

Age-related defects in the auditory system such as hair cell degeneration (leading to high-frequency hearing loss), problems with sound localization, and temporal gap detection in speech contribute to the compromise in speech recognition. Conventional hearing aids offer little help in this regard and cannot group all the sounds from the source of interest into one coherent auditory perception. Audiological tests with a real-time system show marked improvement in speech recognition in many difficult listening conditions (150,151).

A variant of this system utilizes two microphones to process a sound signal biaurally, as occurs in biological systems, which use interaural time differences to localize sound sources (151). Localization of the source azimuths is accomplished by "integration of the locations of temporal coincidence across the broadband of frequencies in speech signals." Once the sound sources are localized, a noise, cancellation scheme is used to suppress all unwanted noise, keeping the gain of the desired signal unchanged. As a result, the device can effectively extract the signal from one particular talker in the presence of four to six competing talkers (150,151).

Increased Use of Assistive Hearing and Amplification Devices, Cochlear Implants, and Other Digital Aids

An important development in the future would be support for the open use of amplification devices, which comes with greater acceptance of the realities of hearing loss (Boxes 5 and 6 and also Chapter 25) (145). A strong preference for conventional hearing-aid use among the elderly shows that even though the sound quality of modern assistive listening devices is preferred over conventional aids, subjects usually are unwilling to endure all of the difficulties associated with the use of remote-microphone devices (145,148).

In a recent report based on interviews with people with presbycusis to analyze individual experiences with usage of hearing-aid technologies, Southall et al. (149) established four

"landmarks" for successful use of technologies to treat hearing impairments:

■ Recognizing problems with hearing

■ Knowledge that the beneficial technology exists

■ Assistance in determining which device to use and acquiring the devices

■ Altering behavior to include usage of the device

The authors recommend that people with hearing problems need to move through these steps; achievement or failure at each step is likely to lead to either successful use of devices or failure to use devices effectively. Hearing therapists should use these guidelines as a framework to obtain a proper device for the patients, and encourage them to use it (149).

BOX 7 Genes, Chromosomes, and Presbycusis

MHC genes and presbycusis. Gene haplotypes in the MHC domain may be associated with the pathogenesis of certain types of hearing loss, including presbycusis. An extended MHC haplotype was identified for unrelated people in a cohort study with strial presbycusis and other types of hearing disorders. In this investigation, 44% of subjects expressed this MHC haplotype, as opposed to 7% of the general population (152).

DFNA25. Linkage analysis by Greene et al. (153) has found a novel, dominant locus, DFNA25, for delayed-onset, progressive, high-frequency, nonsyndromic sensorineural hearing loss of many generations of a U.S. family of Swiss descent. The 20 cM region of chromosome 12q21-24 with possible candidate genes [ATP2A (yeast-like FOFI-ATPase a subunit), ATP2Bl (ATPase, Ca2+ transporting, plasma membrane 1 gene), UBE3B (a member of the E3 ubiquitin ligase family), or VR-OAC (vanilloid receptor-related osmotically activated channel, a candidate vertebrate osmoreceptor)] are implicated.

DFNA5. According to Van Laeret al. (154), over40 loci for nonsyndromic hearing loss have been mapped to the human genome, but only a small number of these genes have been identified. One mutation found in an extended Dutch family is linked to chromosome 7p15 (DFNA5). This mutation has been defined as an insertion or deletion at intron 7 that removes five G triplets from the 3-prime end of the intron while not affecting intron-exon boundaries. This mutation, which is associated with deafness in this family, causes a skip of intron 8, with consequent termination of the open reading frame, and is expressed in the cochlea, but the physiological function is still unknown.

mtDNA4977 deletion. Studies of mitochondrial DNA (mtDNA) by Ueda et al. from cochlear sections of temporal bones of control subjects and those with presbycusis found a specific mtDNA4977 deletion in ~80% of those with presbycusis, compared to half as much in the cochlea of controls (155). Therefore, some of the advanced sensorineural hearing loss cases of presbycusis should be categorized as mitochondrial oxidative phosphorylation diseases, thus offering novel possibilities for treatment and prevention of sensorineural hearing loss, including presbycusis (155).

BOX 8 Recent Models and Animal Studies on Presbycusis

■ NEUROTROPHIN EXPRESSION AND PRESBYCUSIS (175)

1. Two known presbycusis animal models, Fisher 344 rats and Mongolian gerbils, show decreased amounts of brain derived neurotrophic factor (BDNF) mRNA in aging high-frequency cochlear neurons.

2. A reduction in BDNF signaling leads to a decrease in innervation of the outer hair cells of the basal region of cochlea, accompanied with significant hearing loss.

3. Loss of BDNF transcript occurs along a gradient of the cochlea's tonotopic axis, with the highest concentration at the basal, high-frequency end. Loss also occurs in dendrites going toward the brainstem, as well as central cochlear dendrites.

Conclusion: Neurotrophin (e.g., BDNF) are implicated in maintaining the integrity of normally functioning outer hair cells and/or brainstem synapses, and their loss during aging may be related to the presbycusis.

■ DOWNREGULATION OF p-SUBUNIT OF ACETYLCHOLINE RECEPTOR (ACHR) AND NEURONAL LOSS IN SPIRAL GANGLION IS IMPLICATED IN PRESBYCUSIS (176)

1. Nicotinic acetylcholine receptor (nAChR) subunit p2 is required for maintenance of spiral ganglion neurons (primary sensory relays in auditory system) during aging.

2. Hearing loss in p6 p2-/- mice is dramatic, with elevated hearing thresholds across the full range of frequencies.

3. In the spiral ganglion neurons of the auditory system of p2-/- mice, expression of the p2 subunit of AChR is reduced significantly; also, the number of neurons in this ganglion is reduced by 75% in aging, compared to controls.

Conclusion: p2 subunit expression is required for maintenance of spiral ganglion neurons during aging, and its loss may contribute to known presbycusis in this animal model.

■ DELETION OF ANTIOXIDANT ENZYME CU/ZN SUPER OXIDE DISMUTASE CONTRIBUTES TO AUDITORY AGING AND PRESBYCUSIS IN MICE (177,178)

1. At 12 months of age, Sod1 -/- mice have significantly increased thresholds at all frequencies investigated; thresholds at high frequency were 20dB greater than even those observed in the B6 strain mice, known for their presbycusis.

2. Sod1 mice show fewer ganglion cells at all ages investigated; loss occurs more rapidly than age-matched control animals.

3. Hair cells and stria vascularis also are diminished relative to controls.

4. Overexpression of Sod1 did not protect against the aging effects.

Conclusion: Expression of Sod1 enzyme in at least 50% of optimal level is necessary for survival of cochlear neurons and the stria vascularis and to prevent age-related hearing loss.

CALORIC RESTRICTION RETARDS NEURONAL CELL DEATH IN SPIRAL GANGLION PRESBYCUSIS (131)

Caloric restriction (CR) suppresses apoptotic cell death in the spiral ganglia of the mammalian cochlea and prevents late-onset presbycusis. CR mice, maintained at the same weight as young controls, retained normal hearing and showed no cochlear degeneration. Results are thought to be due to downregulation of genes responsible for apoptosis.

■ RECENT REVIEW OF ANIMAL STUDIES (179)

Animal models have proven invaluable in studying genetic as well as environmental causes of aging of the auditory system and presbycusis. Recent animal models of age-related and noise-induced hearing loss have been amply reviewed by Ohlemiller (179).

Assistive Hearing and Amplification Devices

For aging people with mild-to-moderate hearing sensorineural hearing loss (SNHL), conventional hearing aids that basically are amplification devices designed to overcome the high-frequency loss are effective in assisting them to regain hearing ability in a quiet ambience. The efficacy of these aids in many everyday environments, however, is more limited, because the devices typically amplify all sounds in the room, the desired as well as the unwanted sounds. Additionally, these devices cannot restore the hearing ability in people with profound deafness. Modern devices have been developed to specifically address these needs. Among the latest devices, cochlear implants (146) and a new generation of "intelligent hearing aids" can be named (Boxes 5 and 6) (150,151).

128 n Meisami et al. n Genetic Aspects of Presbycusis

Since the 1990s, many studies have focused on genetic aspects of presbycusis. Specifically, several DFNA loci have been determined to exist in relation to inherited deafness and presbycusis, as well as several mitochondrial associated mutations such as mtDNA4977 deletion (Box 7).

General Inheritance of Presbycusis

In a cohort study by Gates et al. (156) to find the prevalence of ARHL inheritance, genetically unrelated (spouses) and genetically related (siblings/parent-child) pairs were compared in regard to patterns of hearing-level groupings. A familial aggregation was definitely found to exist for sensory and strial presbycusis, as well as for those with normal hearing ability. Women showed a stronger aggregation than men, and the strial heritability estimate was greater than the sensory phenotype (156).

Mitochondrial Genetics and SNHL Presbycusis

Acquired mitochondrial defects have been postulated as being key to aging, especially aging of neuromuscular tissues. Mutations in the mitochondrial cytochrome oxidase II gene were found to be common in the spiral ganglion and membranous labyrinth of archival temporal bones of five patients with presbycusis, implicating mitochondrial mutations in at least a subgroup of presbycusis (157). Keithley et al. (158) point out, however, that the cytochrome oxidase defect cannot entirely account for presbycusis. In addition, an association between mitochondrial DNA and presbycusis has been found (155). Patients with SNHL had an increased prevalence for mitochondrial DNA deletion mtDNA4977 (75%) versus 30% in controls. It is proposed that certain SNHL subtypes should be categorized as diseases of mitochon-drial oxidative phosphorylation (Box 7) (155).

Recent Genetic Studies on Hearing Disorders

In a recent review, McHugh and Friedman (159) presented a novel concept that many hearing loss-related genes (including those implicated in presbycusis) are not expressed in a Mendelian pattern but instead are influenced by allelism and modifier genes. Analyses of genes and the vast phenotypic spectrum involved in Usher syndrome as well as Wolfram syndrome indicate that modifier genes are likely playing key roles in the heterogeneity of syndromes involving hearing impairments. Modifier genes, which were previously ignored, appear to be keys to understanding many types of hearing loss including presbycusis.

Garringer et al. (160) recently carried out a linkage analysis of 400 genomic markers of a cohort of 50 pairs of aging fraternal twins (mean age, 73 years) with hearing loss in one or both ears. They found strong evidence for a hearing impairment locus near chromosomal location 3q22, near the recently discovered DFNA18 locus. The latter locus has been implicated in a type of hereditary deafness with progressive ARHL. Results suggest a genetic ink to ARHL in the population.

In a recent case-control study of elderly patients with and without presbycusis in Turkey, Unal et al. (161) noted that the different genotypes of the enzyme N-acetyltransferase 2 (NAT2), which plays key roles in detoxification of cytotoxic, carcinogenic compounds and reactive oxygen species, may be associated with presbycusis; specifically, they found a 15-fold greater risk of presbycusis in patients with NAT2*6A polymorphism.

n Sound Localization and Speech Perception Sound Localization

Tests of sound localization indicate a decline in this ability with aging, beginning in the fourth decade (28). It is known that localization of low-frequency sounds depends on temporal discrimination (i.e., time of sound arrival) between the two ears, while in the high-frequency range, localization depends on discrimination of sound intensity between the two ears. Aging changes occur in both ears, though the rate of aging may be different in the two ears (122,130). Thus, deficits in localization of sound will be apparent for all frequencies, but may be more marked for sounds of higher frequency, as the perception of these are particularly impaired in old age (see above).

Early Studies on Hearing Deficits and Speech Perception

Hearing of consonants vs. vowels

The marked hearing deficits in the high-frequency range have an important bearing on impaired speech perception in the elderly (123,162). Thus, vowels, generated by low-frequency sounds, are heard better than the consonants produced by high-frequency sounds. Similarly, voices of men are heard better than those of women and children, which have a characteristic high pitch. Because consonants make speech intelligible, while vowels make it more audible, a common complaint of the elderly is that they cannot understand spoken words, although they can hear them (28). Fortunately, lip reading, which is associated more with the expression of consonants, can greatly help with this deficiency.

Speech Speed and Comprehension

As indicated in the data of Figure 9, if speech is presented to the aged subjects too fast or with reverberations (i.e., echoing or booming), its comprehension declines markedly. The greatest decline in comprehension is observed if speech is presented with repeated interruptions, such as eight times per second, as is the case with many modem telephone systems (28). This presents an unfortunate situation for the elderly, who rely so much on the telephone for their communication with the outside world.

Sound Masking and Speech Comprehension

The ability to mask sounds, important for speech comprehension in a crowd of talking people, is considerably diminished in

FIGURE 9 Deficits in speech comprehension at different ages. Note that normal aging deficits are exaggerated when speech is presented faster or with reverberations. Source: From Ref. 28, based on the original data of Ref. 163.

FIGURE 9 Deficits in speech comprehension at different ages. Note that normal aging deficits are exaggerated when speech is presented faster or with reverberations. Source: From Ref. 28, based on the original data of Ref. 163.

the elderly. Indeed, tests of hearing loss for pure tones provide usually conservative estimates of hearing deficits, because the tests are usually performed under quiet laboratory conditions, eliminating the need for masking. One example of loss of masking ability with age is the increase, with advancing age, in reporting the incidence of ringing in the ear (tinnitus), even though this problem is manifested at all ages. Perhaps the elderly cannot mask these unusual sounds, while the young can (28).

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