Auditory Brainstem Dysfunction,Non-Invasive Biomarkers for Early Diagnosis and Monitoring of Alzheimer’s Disease in Young Urban Residents Exposed to Air Pollution

Abstract

Alzheimer’s disease (AD) is a biological construct defined by abnormal deposits of hyperphosphorylated tau and amyloid-β. The 2050 projection for AD in the USA is 14 million. There is a strong association between AD, air pollution, and traffic. Early diagnosis is imperative for intervention in the initial disease stages. Hearing and, specifically, the ability to encode complex sounds are impaired in AD. Nuclei in the auditory brainstem appear to be sensitive to neurodevelopmental and neurodegenerative disorders. Specifically, sustained exposure to air pollution is harmful to the brainstem; young residents of Metropolitan Mexico City (MMC) exposed to fine particulate matter and combustion-derived nanoparticles develop AD pathology in infancy. MMC clinically healthy children and teens have significant central delays in brainstem auditory evoked potentials (BAEPs). Herein, we review evidence that the auditory pathway is a key site of AD early pathology associated with air pollution and is significantly involved in AD patients. We strongly suggest electrophysiological screening, including BAEPs, be employed to screen individuals for early delays and to monitor progressive decline in patients diagnosed with mild cognitive impairment and AD. Understanding auditory dysfunction in early AD in pediatric and young adult populations may clarify mechanisms of disease progression. Air pollution is a risk factor for the development of AD and as the number of Americans with AD continues to grow without a cure, we need to focus on preventable, early causes of this fatal disease and intervene appropriately.

Keywords

Air Pollution alzheimer’s continuum alzheimer’s disease amyloid-β brainstem evoked potential cochlear combustion-associated nanoparticles fine particulate matter hearing hyperphosphorylated tau neurofibrillary tangles vestibular nuclei

INTRODUCTION

Alzheimer’s disease (AD) is defined by its underlying pathological processes that can be documented by postmortem examination or in vivo by biomarkers [1]. In the National Institute of Ageing and the Alzheimer’s Association Research Framework, the vision is defining AD as a biological construct that will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment associated with AD [1]. Hyperphosphorylated tau (H-Tau) and amyloid-β plaques define AD as a unique degenerative disease [1]. Strong interactions between harmful environments, systemic and neural inflammatory, immunological and metabolic responses are likely at play in the development of AD. While there are a number of well-known risk factors, including aging, APOE4 genotype, Down syndrome, traumatic brain injury, etc., exposure to environmental pollution seems to be a particularly potent risk factor [2 –13].

The association between AD and traffic and air pollution is clear [12–13]. There is a strong association between exposures to fine particulate matter (PM_2.5) and a 138% increased risk of AD per increase of 4.34μg/m³ above the USEPA PM_2.5 standard (12.0μg/m³ annual mean averaged over 3 years) [12]. A population-based cohort study, by Chen and co-workers, included all adults aged 20–50 years (∼4.4 million) and all adults aged 55–85 years (∼2.2 million) who resided in Ontario, Canada [13]. In an 11–year period (2001–2012), these authors identified 243,611 incident cases of dementia. The adjusted hazard ratio of incident dementia was 1.07 for people living less than 50 m from a major traffic road, 1.04 for 50–100 m, 1.02 for 101–200 m, and 1.00 (0.99–1.01) for 201–300 m versus further than 300 m [13]. Thus, exposure to air pollution would be a modifiable risk factor for AD, or at the very least a risk factor that could be regulated/controlled.

In highly exposed Metropolitan Mexico City (MMC) infants, H-Tau neurites are first seen in the lower medulla, and by the second decade, neurofibrillary (NFT) tangles are present in spinal trigeminal, locus coeruleus, cochlear and vestibular nuclei [10]. Interestingly, swallowed combustion-derived nanoparticles gain access to the gastrointestinal epithelium and submucosa, damaging gastrointestinal barrier integrity and accessing the enteric nervous system, a pathway we had strongly suggested permits nanoparticles to reach preganglionic parasympathetic fibers, the vagus nerve, and the lower medulla [9].

We will review the evidence that brainstem auditory pathways are impacted early in AD, that this pattern appears in young individuals exposed to concentrations of PM_2.5 above current USEPA standards and combustion-derived nanoparticles [11], and finally that non-invasive evaluation of auditory function could and should be used to screen for both early diagnosis and progression of AD.

The ultimate goals of AD research are to lessen the burden of the disease and improve quality of life by prevention or slowing progression. To accomplish these, it is essential to identify all risk factors, develop strategies for early detection of the disease development and progression (AD continuum), to be able to intervene, and to monitor the results of the interventions.

THE AUDITORY SYSTEM

The mammalian auditory system begins with an externally arranged sound collecting device (the external ear), a sound conducting apparatus (the tympanic membrane and middle ear ossicles in the middle ear), mechano-receptive hair cells along the organ of Corti in the cochlea, neurons of the spiral ganglion (Fig. 1A) and an exquisitely complex neural circuitry extending from the medulla oblongata to the cerebral cortex (Fig. 1). Despite this complexity, the auditory pathways are arranged according to the principle of sound frequency, or tonotopy. This tonotopic arrangement is established in the cochlea and extends all the way to the cerebral cortex. The primary functions of the auditory system are to detect and convert air pressure waves into action potentials and characterize the frequency, intensity, envelope, and origin of sounds.

Fig.1

The human auditory pathway. The peripheral auditory system includes the external ear, the middle ear (ME), the cochlea, and organ of Corti. The central ascending auditory pathway (A) begins with the spiral ganglion and the auditory nerve (AN). The auditory nerve innervates the dorsal and ventral cochlear nuclei (DCN and VCN, respectively). The VCN projects bilaterally to the nuclei of the SOC and to the contralateral IC (blue arrows). The SOC projects bilaterally to the IC through the lateral lemniscus (LL, black arrows). The IC projects to the MG (green arrows), which in turn projects to the primary auditory cortex (A1, orange arrows). The descending auditory pathway (B) begins in the cerebral cortex and descends to all levels of the pathway (red arrows). The final neurons in the pathway are found in the SOC and project via the olivocochlear bundles (OCB) to the cochlea.

The central auditory pathway begins with bipolar neurons in the spiral ganglion. These neurons send a peripheral axonal projection to innervate inner hair cells and a central axonal projection to the ipsilateral cochlear nucleus (CN) via the auditory nerve (Fig. 1A). The spiral ganglion contains two types of ganglion cells, type I and type II. Type I axons form the major relay from inner hair cells to the brainstem; type II ganglion cells form only a minor population and innervate outer hair cells. Each type I axon terminates widely in the ipsilateral CN. An ascending branch terminates in the anteroventral cochlear nucleus (AVCN) and a descending branch terminates in both the posteroventral cochlear nucleus (PVCN) and the dorsal cochlear nucleus (DCN). The AVCN and PVCN together comprise the VCN and in humans contains approximately 72,000 neurons [14]. From the VCN there are two main streams of information (Fig. 1A, blue arrows): one that innervates both the ipsilateral and contralateral superior olivary complex (SOC) and one to the contralateral inferior colliculus (IC). The projection from the VCN to the IC arises from stellate and multipolar neurons and the projections to the SOC and to the nuclei of the lateral lemniscus (NLL) arise from octopus cells and both globular and spherical bushy cells. The SOC is a collection of nuclei that extends from the rostral medulla to the caudal pons and plays important roles in sound source localization and encoding temporal features of sound. The human SOC contains seven distinguishable nuclei and approximately 35,000 neurons [15, 16]. Animal studies indicate that each of these cell groups comprise a unique neural circuit and role in auditory processing. The SOC include two principle nuclei, the medial superior olive (MSO) and the lateral superior olive (LSO). The size of these nuclei varies considerably across mammalian species. The size of the LSO is indicative of hearing range [17] but the MSO is best developed in species with excellent low-frequency hearing. Humans are excellent low-frequency listeners and have a comparatively large MSO [15]. The human MSO is composed of a thin column of neuronal cell bodies, that form both a medial and lateral dendritic arbor (Fig. 2A, arrowheads) [15]. The structure of MSO dendrites is essential to their function as they collect excitatory input from the right and left VCN and inhibitory inputs from the medial and lateral nuclei of the trapezoid body. From these symmetric inputs, MSO neurons calculate an interaural time difference, a comparison of the arrival time or phase differences between the two ears; this calculation is an important aspect of the localization of sound sources. As such, normal structure and function of the SOC and MSO are required for normal hearing, and neuron loss in the SOC can severely impact hearing.

Fig.2

Pollution induced changes in the MSO. Shown in A are reconstructions of human MSO neurons stained by silver impregnation. The white arrowheads indicate medial and lateral dendrites. Shown in B-E are pictures of 5μm H&E sections of the human MSO. Figure B is from a non-exposed subject. Black arrows indicate typical MSO somata; white arrowheads indicate dendritic profiles which extend hundreds of microns from the soma. Shown in C-E are fields from the MSO of 3 different human subjects exposed to air pollution. Typical MSO soma and dendritic profiles are rare. Pollution exposure results in smaller, round cell body profiles (blue arrows) and cell bodies with abnormal orientation (yellow arrows). The scale bars are equal to 20μm.

In our study of over 78 non-pathological human brainstems ranging from 2 to 96 years of age, the number of neurons in the MSO appears to be stable at ∼13,000 neurons [15 , 19]. We interpret this observation to suggest that the MSO is not susceptible to age-related degeneration and that loss of MSO neurons would be related to neurodegenerative processes. Consistent with this observation, we have observed significant loss of neurons in autism spectrum disorder, Fragile X syndrome, chromosome 15q duplications [15 , 19], and MSO loss has been observed in sudden infant death syndrome [21].

Axons from the MSO, LSO, and many periolivary cell groups ascend in the lateral lemniscus (LL; Fig. 1A, black arrows). Within the axons of the LL are a number of cell groups, known collectively as the NLL. The majority of neurons in the NLL are inhibitory and the vast majority of axons in the LL are destined for the IC. The IC forms a prominent elevation along the posterior aspect of the midbrain and is divided into three major subdivisions, the external cortex, the dorsal cortex, and the central nucleus of the IC (CNIC). The dorsal cortex receives a major projection from the cerebral cortex, and the retina but only sparse inputs from lower auditory centers. The external cortex receives inputs from the somatosensory regions and the CNIC. The CNIC is an essential relay along the ascending auditory pathway and receives input from the DCN, VCN, SOC, and NLL. The human CNIC appears to contain nearly six times as many neurons as the VCN and SOC combined and highlights the complexity and processing that must occur in the auditory midbrain. Axons from the CNIC course through the brachium of the IC (Fig. 1A, green arrows) and target the ventral division of the medial geniculate (vMG). Like the CNIC, the vMG is an essential relay for ascending auditory information directed towards primary auditory cortex (A1). From the vMG, information ascends through the internal capsule to reach A1 and surrounding auditory cortical fields (Fig. 1, orange arrows).

The auditory system is unique in having a very well-developed descending pathway that originates in auditory regions of the cerebral cortex (Fig. 1B, red arrows). This descending pathway involves nuclei at each level of the pathway and ends with axon terminals in the organ of Corti (see [22] for a detailed review). The terminal neurons in this descending pathway are situated in the SOC and form two distinct systems: a medial olivocochlear system and a lateral olivocochlear system. Neurons of the medial olivocochlear system are situated along the ventral and medial aspect of the SOC and send axons to innervate the VCN and outer hair cells in the organ of Corti. The function of this pathway appears to be filtering out background noise when listening in noisy environments. Neurons of the lateral olivocochlear system are located within or around the LSO. lateral olivocochlear system neurons project their axons to the cochlea and terminate on type I auditory nerve axons. It is clear that the olivocochlear bundle (Fig. 1B) modulates function of the cochlea and this modulation plays a key role in protecting the cochlea from sound damage and helps selective listening in the presence of background noise.

NON-INVASIVE PHYSIOLOGICAL TESTS OF AUDITORY FUNCTION

The acoustic stapedial reflex (ASR), otoacoustic emissions, and auditory evoked potentials (AEP) are non-invasive tests used to assess the integrity of the auditory pathways. The major utility of these assessments is that they provide a quick, non-invasive and objective measure of auditory function in children and adults. Accordingly, it had been believed for many years that non-invasive electrophysiological assessments of auditory function can be used to screen for brainstem lesions and disorders [23, 24].

The ASR is initiated by high intensity sounds and requires a three or four neuron brainstem circuit that includes the spiral ganglion, the CN, the SOC, and stapedial motor neurons [24, 25]. The ASR results in reflexive contraction of the stapedius muscle, which attenuates vibration of the stapes and is believed to protect inner hair cells from sound-induced injury and filter out background noise [27]. Thus, the ASR is a noninvasive and objective measure of auditory brain stem function.

AEPs are used to examine the functional integrity of the central auditory pathway extending from the spiral ganglion to the cerebral cortex. The brainstem AEP (BAEP) examines the brainstem components of the pathway. BAEP responses are present postnatally, and are not impacted by anesthesia or attentional state, and provide a quick, non-invasive measure of brainstem function [28]. The BAEP response includes five peaks, numbered I through V and these waves are believed to result from synchronous activity within the major brainstem centers (Fig. 1). Waves I and II correspond to activity in the auditory nerve. Wave III is related to activity in the CN and SOC. Wave IV is associated with activity in the nuclei of the lateral lemniscus and wave V corresponds to the IC [29]. The BAEP is followed in time by middle latency responses which include waves Na, Pa, Nb, and P1 (P50), and these waveforms are believed to be generated by both brainstem and thalamic centers [30]. Finally, following the middle latency responses are the late auditory evoked potentials and these include P100, N100 (N1), P200 (P2), N200 (N2), P300, N400, and P600. These waves correspond to activity in the auditory cortex and associated temporal lobes [30]. In summary, the AEPs consist of a series of waves that can be recorded from scalp electrodes and are derived from synchronous electrical activity from the many components of the auditory pathway. Accordingly, changes in the latency and amplitude of these waves are associated with dysfunction along the auditory pathway.

Nearly fifty years ago, it was discovered that the cochlea could form sound pressure waves and that these sound waves could be recorded from the external ear [31]. These sounds created by the cochlea are termed OAEs, are produced by contraction of outer hair cells, and require normal structure and function of the external ear, middle ear and cochlea. Accordingly, OAEs serve as an additional simple and objective measure of cochlear function.

ALZHEIMER’S DISEASE AND AUDITORY DYSFUNCTION

The literature provides clear evidence for dysfunction in central auditory processing in AD and this dysfunction appears to precede the signature cognitive decline of AD [32 –49]. The involvement of the auditory system in AD has been demonstrated by a combination of postmortem studies, audiometry, AEP, and psychoacoustics. However, much of the work done on hearing in subjects with AD has focused on cortical structures and tests of higher-level auditory processing. Herein, we will review the literature supporting auditory dysfunction in AD, evidence for early involvement and the negative impact that chronic exposure to air pollution has on auditory brainstem centers.

Postmortem examination of brain tissue from subjects diagnosed with AD has revealed marked pathological changes in the auditory system. In a sample of 7 subjects with AD, Congo Red positive amyloid plaques were identified in the CNIC and silver positive NFT were found in the DCN, SOC, NLL, and CNIC [32]. Another study revealed both plaques and NFT in the CNIC, vMG, and auditory cortex in 9 of 9 subjects [33]. Sinha and coworkers also reported widespread neuronal loss in the CNIC and vMG but found no significant changes in the CN or adjacent, non-auditory structures. Additionally, morphological study of the CNIC and vMG in 12 AD patients revealed significant neuron loss and reduced dendritic spines [34]. There does not appear to be a consensus on the involvement of the cochlea in AD. Some studies find evidence for changes in hearing thresholds or peripheral hearing sensitivity [35 , 39], while others find no change in AD [36 , 45]. While not significant, there does also appear to be a trend toward fewer cochlear hair cells and fewer neurons in the spiral ganglion in AD patients [33]. Additionally, OAEs [36] and ASRs [40] are reported as normal in AD.

Psychoacoustic and electrophysiological testing raised the suspicion for auditory dysfunction in AD over 30 years ago. Specifically, AD patients have difficulty with dichotic listening [41 –43], processing of verbal stimuli in the presence of background noise [36, 46], and significant impairment and asymmetric hearing sensitivity [43]. We propose that such difficulties with listening in the presence of background noise might be attributed to dysfunction in the olivocochlear bundle (Fig. 1B). More recent studies provide evidence for impaired sound localization [37, 39] and asymmetric auditory processing issues [47] in AD. Subjects with AD show abnormal cortical activation in response to spatial stimuli but normal activation to simple sounds [50]. Golden and co-workers’ observation suggests that, at least in cortical areas, there is a preferential impact on circuits dedicated to complex processing of sound. Further supporting the connection between central auditory processing abnormalities and AD are results showing a relationship between performance on psychoacoustic evaluations, levels of AD biomarkers in the CSF and MRI-based measures of entorhinal and hippocampal cortex volumes [48].

Most electrophysiological assessments of AEP have focused on middle and late responses and changes in amplitude and latency of these waves are a consistent finding in AD (reviewed in [51]; see also [35, 52]). In fact, a recent review provides evidence that changes in P300 and N200 waves distinguish normal aging from AD [53]. Further, studies of brainstem AEPs provide evidence for delayed inter-wave I-V and Pa [54, 55], although other studies failed to identify any significant changes in BAEPs in subjects with AD [41, 56]. Nevertheless, more recent studies suggest that difficulties with auditory processing might be a marker for early/pre-symptomatic AD [38 , 48] and that more severe hearing impairment is associated with lower cognitive function [44]. Indeed, it has been suggested that auditory processing issues precede the onset of AD by 5 to 10 years [47] and performance on audiometric word identification tasks was able to predict dementia within four years of the test [39]. Auditory assessment with verbal tasks has been recommended by researchers to screen older patients and especially those with suspected or high risk dementia [36]. Together, these findings provide strong evidence for significant structural and functional changes along the auditory pathway in AD and suggest that auditory and/or speech testing might provide a simple, low-cost, and non-invasive screening tool.

There is strong recent evidence for significantly higher risk of AD in young subjects exposed to fine particulate matter and combustion-derived nanoparticles [10, 11]. In a recent study of 203 consecutive autopsies of 1–40–year-old subjects (average age 25.36±9.23 y) chronically exposed to airborne particulate matter (as residents in MMC) and otherwise healthy before death and without any evidence of extra-neural pathology revealed a shocking result [10]. These subjects from Mexico City showed markers of AD pathology in 99.5% of cases: H-Tau positive neurites, NFT, and amyloid-β plaques, and 11-month-old infants exhibited H-Tau neurites in the lower medulla, including the reticular formation, dorsal motor nucleus of the vagus, and spinal trigeminal nucleus. Subjects in the second decade had H-Tau neurites, cytoplasmic H-Tau, and brainstem NFT in the central and periaqueductal gray, locus coeruleus, medial lemniscus, IC, DCN, and vestibular nuclei. By the 3rd and 4th decades of life, subjects were classified as NFT stage III-V, with extensive brainstem pathology. Of particular interest, H-Tau was found in the IC and CN in subjects all through the 2nd to 4th decades of life [10]. Brainstem inflammation and extensive auditory nuclei pathology have been described in MMC children ages 8.02±0.7 years [57]. A sharp contrast in the morphology of MSO neurons between children residing in low polluted places and MMC is a key finding [57]. The SOC also showed markers of oxidative stress, accumulation of amyloid-β and in MSO neurons, statistically significant differences in cell body area, perimeter, major axis, and circularity versus clean air controls were documented [57]. Strikingly, immunoreactivity to aggregated pathological forms of alpha-synuclein, recognized as mediator of Parkinson’s disease pathogenesis, was seen in DCN, vestibular, spinal trigeminal, dorsal motor nucleus of the vagus, and several ascending and descending brainstem tracts. It is clear that children with high levels of exposure to air pollution, both hallmarks of Alzheimer’s and Parkinson’s diseases are present, bringing the issue of a common denominator for both complex neurodegenerative diseases [57, 60]. Relevant to this review from the clinical point of view is the fact that healthy MMC children ages 8.02±0.7 years with unremarkable clinical histories, versus age-matched children from a control city with all criteria pollutants (ozone, particulate matter, SO₂, NO₂, CO, and Pb) below USEPA standards, had significant central delays in brainstem AEPs. Specifically, children from Mexico City showed no delay in wave I but had significantly longer latencies in wave III, wave V, and interwaves I-V, III-V, and I-V (González-González, unpublished results). These results suggested normal conduction along the auditory nerve, and preservation of the cochlea and spiral ganglion, but significant delays in conduction along auditory brainstem pathways. Specifically, the delay in interwaves suggests impaired conduction from the CN to the CNIC. Clearly, humans are not isolated in terms of auditory effects; Mexico City dogs showed exactly the same spectrum of auditory pathology and central delayed brainstem AEPs [61]. Strikingly, young dogs showed VCN hypotrophy and MSO dysmorphology along with significant delays in brainstem AEPs [61].

Despite variable results of BAEPs in AD, subjects exposed to air pollution appear to have more consistent and reliable changes in brainstem responses. Significant delays in BAEPs and converging brainstem pathology in both children and young dogs— a combination of oxidative stress, abnormal protein accumulation, inflammation, and morphometric changes in targeted auditory nuclei—strongly supports the argument of using BAEPs, acoustic stapedial reflex, and otoacoustic emissions as non-invasive tests to assess the integrity of the auditory pathways, identify early brainstem involvement in the progression of AD pathological changes and more importantly, if interventions are in place, follow their response to treatments.

SUMMARY AND CONCLUSIONS

There is abundant evidence for early brainstem changes in AD and these changes appear to target auditory brainstem pathways. Certainly in children chronically exposed to air pollution, the auditory brainstem shows an early accumulation of H-Tau, amyloid-β, evidence of oxidative stress, dysmorphology, and significant delays of BAEPs. Accordingly, non-invasive physiological assessment of these brainstem pathways may serve as an early screening tool. Recording of AEPs is non-invasive and will guide clinicians regarding individual risk. In fact, repeat testing of those facing chronic exposure to air pollution and/or at risk of AD might serve an important role in early detection and intervention. Understanding auditory dysfunction in early AD in pediatric and young adult populations may shed light on the mechanisms of disease progression. Air pollution is a modifiable risk factor for AD and as the number of Americans with AD grows fast, we need to focus on preventable, early causes of this fatal disease and intervene appropriately.

Footnotes

ACKNOWLEDGMENTS

The work was supported by Lake Erie Consortium for Osteopathic Medical Training and the SEP-CONACYT 255956 G7 CB-2015-01.

Authors’ disclosures available online ().

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