doi:10.1093/brain/awaa429
BRAIN 2021: 144; 391–401
| 391
UPDATE
Hearing and dementia: from ears to brain
Jeremy C. S. Johnson,1 Charles R. Marshall,1,2
Chris J. D. Hardy1,† and Jason D. Warren1,†
These authors contributed equally to this work.
The association between hearing impairment and dementia has emerged as a major public health challenge, with significant opportunities for earlier diagnosis, treatment and prevention. However, the nature of this association has not been defined. We hear with
our brains, particularly within the complex soundscapes of everyday life: neurodegenerative pathologies target the auditory brain,
and are therefore predicted to damage hearing function early and profoundly. Here we present evidence for this proposition, based
on structural and functional features of auditory brain organization that confer vulnerability to neurodegeneration, the extensive,
reciprocal interplay between ‘peripheral’ and ‘central’ hearing dysfunction, and recently characterized auditory signatures of canonical neurodegenerative dementias (Alzheimer’s disease, Lewy body disease and frontotemporal dementia). Moving beyond any simple dichotomy of ear and brain, we argue for a reappraisal of the role of auditory cognitive dysfunction and the critical coupling of
brain to peripheral organs of hearing in the dementias. We call for a clinical assessment of real-world hearing in these diseases that
moves beyond pure tone perception to the development of novel auditory ‘cognitive stress tests’ and proximity markers for the
early diagnosis of dementia and management strategies that harness retained auditory plasticity.
1 Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University
College London, London, UK
2 Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK
3 Movement Disorders Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology,
University College London, London, UK
4 Wellcome Centre for Human Neuroimaging, UCL Queen Square Institute of Neurology, University College London, London, UK
5 UCL Ear Institute and UCL/UCLH Biomedical Research Centre, National Institute for Health Research, University College London,
London, UK
Correspondence to: Prof Jason Warren
Dementia Research Centre
UCL Queen Square Institute of Neurology
University College London
8–11 Queen Square
London WC1N 3BG, UK
E-mail: jason.warren@ucl.ac.uk
Keywords: hearing; dementia; Alzheimer’s disease; frontotemporal dementia; Lewy body disease
Introduction: scope and
nature of the problem
Hearing impairment in later life is a major clinical issue and
a leading association of cognitive decline (Gates and Mills,
2005; Lin et al., 2011; Loughrey et al., 2018), presenting
significant potential opportunities for dementia diagnosis,
treatment and prevention (Dawes et al., 2015; Taljaard
et al., 2016; Livingston et al., 2017). But how are hearing
impairment and dementia related? Hearing loss of any
Received August 14, 2020. Revised October 2, 2020. Accepted October 17, 2020. Advance access publication December 22, 2020
C The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,
distribution, and reproduction in any medium, provided the original work is properly cited.
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
†
Rimona S. Weil,1,3,4 Doris-Eva Bamiou,5
392
| BRAIN 2021: 144; 391–401
manifestation of canonical dementia syndromes. We propose
a roadmap for future work directed towards developing
novel auditory cognitive tests, biomarkers and therapies.
The auditory brain:
structural and functional
substrates for
neurodegeneration
The auditory system has evolved to allow adaptive behavioural responses to complex, dynamic acoustic environments
(Griffiths et al., 2001; Pickles, 2015). However, its structural
and functional characteristics confer specific vulnerabilities
to neurodegenerative pathologies.
Anatomically, the hierarchy of auditory processing relays
and in particular the large-scale cerebral networks that process sound information (Fig. 2) are highly distributed. The
spread of pathogenic proteins in neurodegenerative dementias (Fig. 2) targets these networks rather than the peripheral
organs of hearing. Though histopathological data remain
limited, neurodegenerative pathologies may preferentially involve auditory association cortex and cortico-cortical projections rather than primary sensory cortex (Esiri et al., 1986;
Lewis et al., 1987), thereby striking the integrative mechanisms that are most critical for auditory object analysis.
Accurate auditory signal transduction (for example, during
spatial hearing or speech perception) depends on precise integration of frequency-based (spectral) and time-based (temporal) information (Griffiths et al., 2001; Bizley et al.,
2009): any pathology that damages relevant neural circuits
is likely to disrupt such processing early in its course. As the
auditory signal passes up the processing hierarchy, it is
transformed non-linearly such that it is no longer a direct
replica of the incoming signal encoded at the periphery
(Wang, 2007; Gaucher et al., 2013); due to the intrinsically
temporal nature of sound, this transformation of auditory
information is particularly evident in the time domain and
supports the extraction of invariant auditory object features
and cross-modal integration. The resulting percept is normally robust to noisy variations in the sensory signal; however, its non-linear nature means that even small
perturbations of neural circuit function due to neurodegenerative disease may have disproportionately large perceptual
and behavioural consequences.
Two additional, related guiding principles of auditory system
operation that are critical for adaptive functioning in complex,
dynamic auditory environments are functional plasticity and
reciprocity. Reciprocity is mediated by recursive, afferent-efferent feedback that supports auditory change detection and topdown tracking of behaviourally relevant sound sources
(Shamma and Micheyl, 2010; Zion Golumbic et al., 2013), as
well as predictive decoding and ‘filling-in’ of ambiguous and
varying auditory inputs, such as degraded speech (Malmierca,
2014; Simon, 2015; Donhauser and Baillet, 2020) (Fig. 1).
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
cause tends to limit social engagement and quality of life
(Graydon et al., 2019), amplifies the effects of cognitive impairment and may confound or delay diagnosis of dementia
(Panza et al., 2015; Wayne and Johnsrude, 2015).
Conversely, diagnosis of hearing loss and compliance with
hearing aids are hindered by cognitive impairment (Dawes
et al., 2015). There may, however, be a more fundamental
pathophysiological basis for the association: hearing is a
complex cognitive function that, alongside other cognitive
functions, is directly vulnerable to the pathophysiological
processes that cause dementia (Wayne and Johnsrude, 2015;
Hardy et al., 2016).
Recent studies addressing the link between hearing impairment and dementia have focused predominantly on audiometric pure tone detection, the ability to detect quiet sounds
(Lin et al., 2011; Loughrey et al., 2018). However, most natural auditory environments or ‘scenes’ comprise mixtures of
sounds that change over time, and listening—perception and
understanding of sounds—is a highly active cognitive process (Bendixen, 2014) (Fig. 1). Consider, for example, the
everyday scenario of following a conversation in a crowded
room. After substantial ‘pre-cognitive’ processing in the
auditory brainstem (Cope et al., 2015), the incoming auditory signal must be deconstructed (by ‘auditory scene analysis’) (Goll et al., 2012a; Golden et al., 2015c; Hardy et al.,
2016) into discrete and stable percepts or ‘auditory objects’
corresponding to voices and speech features, separate from
background noise (Griffiths and Warren, 2004; Goll et al.,
2010b). Such auditory objects must be matched to stored
representations and expectations to achieve recognition and
ultimately, an appropriate behavioural response. These processes collectively constitute ‘auditory cognition’ (Fig. 1) and
depend critically on neural computations in auditory cortical
and linked processing networks: the auditory brain (Fig. 2).
Evidence that neurodegenerative pathologies target the
auditory brain and produce ‘central’ hearing deficits disproportionate to any peripheral hearing loss was first produced
some time ago (Kurylo et al., 1993; Strouse et al., 1995).
More recently, a diverse array of ‘central’ auditory deficits
has been described in these diseases (Mahoney et al., 2011;
Rohrer et al., 2012; Fletcher et al., 2015, Golden et al.,
2015c; Grube et al., 2016; Hardy et al., 2016; Eversfield
and Orton, 2019; Jafari et al., 2020), ranging widely beyond
‘deafness’ (impaired sound detection) to encompass altered
auditory perception, understanding and behavioural
responses, with far-reaching consequences for hearing function in daily life. To date, however, the role of the auditory
brain in linking hearing impairment to cognitive decline has
been largely overlooked.
Here we argue that the auditory brain is integral to the development and expression of hearing impairment in dementia. Our case rests on three interwoven lines of evidence: the
structural and functional characteristics of auditory brain organization targeted by neurodegenerative diseases; the
known extensive interplay between so-called ‘peripheral’ and
‘central’ hearing mechanisms; and mounting data on auditory cognitive dysfunction as a prominent, early and specific
J. C. S. Johnson et al.
Hearing and dementia: from ears to brain
BRAIN 2021: 144; 391–401
| 393
Plasticity (for example, perceptual learning of degraded speech)
(Hardy et al., 2018) enables dynamic neural adaptation to auditory experience.
These functional principles are evident throughout the
auditory system (Russo et al., 2005; Barascud et al., 2016;
Guinan, 2018) and are highly sensitive to synaptic neurochemical (particularly cholinergic) modulation, especially
under challenging listening conditions (Dhanjal et al., 2013;
Kuchibhotla et al., 2017; Minces et al., 2017). They are
therefore potentially highly susceptible to neurodegenerative
pathologies that disrupt synaptic and neurotransmitter pathway integrity. Moreover, the characteristics of non-linear
stimulus coding, extensive efferent regulation of afferent
pathways and pervasive plasticity (though not specific to audition) are much more marked in the auditory system than
in other sensory systems, notably vision (King and Nelken,
2009). Impaired functional adaptation of auditory brainstem
pathways has perceptual consequences in patients with mild
cognitive impairment (Bidelman et al., 2017), suggesting that
indices of auditory plasticity may be sensitive and dynamic
markers of neurodegenerative pathologies.
‘Peripheral’ and ‘central’
hearing: a false dichotomy
and a double hit
The anatomical and functional interactions of auditory processing stages (Figs 1 and 2) suggest that any sharp distinction between ‘peripheral’ and ‘central’ hearing is likely to be
a false dichotomy. Pure tone audiometry (PTA), the
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
Figure 1 Processes and interactions in ‘peripheral’ and ‘central’ hearing. The functional organization of the auditory processing hierarchy and the interplay of hearing with more general cognitive functions. Ellipses indicate the broad domains of peripheral hearing (blue; anatomically, the peripheral hearing apparatus which receives incoming sounds, cochlea and auditory nerve), precognitive auditory processing (green;
chiefly the auditory brainstem), auditory cognition (yellow; auditory cortex and its cerebral connections) and general cognitive functions (red;
see Fig. 2 for neuroanatomy). Listed within the ellipses are some key stages in the analysis of auditory information: ‘peripheral’ and ‘central’ hearing processes lie on a functional and anatomical continuum, with reciprocal connections between successive processing stages (black arrows).
This organization implies that pathologies (such as neurodegenerative proteinopathies) predominantly targeting auditory cognitive (and general
cognitive) processing stages may have cascading effects at other processing stages. Certain additional functional properties that operate across
auditory processing stages, such as non-linear signal coding and plasticity, are likely to be particularly vulnerable to the effects of neurodegenerative pathologies (see text). External red and blue arrows here signify general mechanisms by which hearing dysfunction of any cause may promote
cognitive decline, and the converse; these mechanisms are likely to be mutually reinforcing and may additionally compound more specific effects
of auditory brain dysfunction, with the potential to establish pathophysiological ‘vicious cycling.’
394
| BRAIN 2021: 144; 391–401
J. C. S. Johnson et al.
pinning hearing (Fig. 1) as spheres overlaid in a left lateral view of the brain. These regions are anatomically and functionally linked into large-scale,
distributed networks. The colour convention follows that in Fig. 1 (green, precognitive auditory processing in brainstem pathways, enclosed by
the grey filled outline; yellow, auditory cognition in auditory cortices; red, general cognitive processes in connected cerebral regions); note,
however, that there is no simple, one-to-one correspondence between particular brain regions and individual ‘tiers’ of the processing hierarchy outlined in Fig. 1. Brain regions are designated as follows: ATL = antero-mesial temporal lobe (also encompassing amygdala and hippocampus); CN = cochlear nucleus (ventral and dorsal); HG = Heschl’s gyrus (medial portion contains primary auditory cortex); IC = inferior
colliculus; IFG = inferior frontal gyrus (closely associated with insular cortex, deep to the cerebral surface); IPL = inferior parietal lobe; ITC
= inferior temporal cortex; MGB = medial geniculate body; MTG = middle temporal gyrus; OFC = orbitofrontal cortex; PFC = prefrontal
cortex; SO = superior olive (its main projection in the lateral lemniscus has several additional, small associated nuclei); STG = superior temporal gyrus; TPJ = temporo-parietal junctional cortex. Also shown in grey filled outline is the cingulate gyrus, projected from the medial surface of each cerebral hemisphere: this signifies linked deep medial prefrontal and parietal cortices that also participate importantly in
integrative and modulatory cognitive processes relevant to hearing. (B) Key components of the brain networks implicated in hearing that are
also predominantly targeted in representative neurodegenerative proteinopathies. These patterns of brain degeneration anticipate the differential involvement of particular auditory functions and therefore distinctive functional hearing profiles or ‘auditory phenotypes’ of these disorders (see text and Table 1). Although the neuroanatomical patterns shown correspond to the distribution of most severe regional brain
atrophy in each disease, dysfunction predates atrophy and additional connected brain regions may also be implicated in the pathogenesis of
auditory symptoms. AD = typical Alzheimer’s disease; nfvPPA = non-fluent agrammatic variant primary progressive aphasia; svPPA = semantic variant primary progressive aphasia.
mainstay of standard clinical audiological assessment, is generally interpreted as an index of ‘peripheral’ (cochlea and
auditory nerve) hearing. However, PTA thresholds are
affected by attention (Musiek et al., 2017), executive function (Gates et al., 2010) and brainstem pathologies that do
not directly involve the cochlea (Cope et al., 2015), reflecting
the known role of top-down influences on cochlear sensitivity (Terreros and Delano, 2015). Furthermore, PTA does not
fully predict ability to hear speech in noise (the principal
hearing complaint of older listeners) (Anderson et al., 2011;
Guest et al., 2018; Holmes and Griffiths, 2019). Conversely,
‘central’ hearing functions that rely on high-fidelity signal
coding at brainstem level (such as speech intelligibility) are
tuned by efferent synaptic functional adaptation at the
cochlea (Pressnitzer et al., 2008) and auditory agnosia is
modulated by peripheral hearing loss (Coebergh et al.,
2020). Neurodegenerative diseases that principally involve
cortical and subcortical pathways may therefore significantly
impact hearing functions canonically attributed to the peripheral sense organs; indeed, elevated PTA thresholds have
recently been documented in the non-fluent agrammatic variant of primary progressive aphasia (nfvPPA), a primary cortical degeneration (Hardy et al., 2019). On the other hand,
anatomical involvement of subcortical auditory relays by
neurodegenerative pathology does not necessarily lead to a
perceptual deficit (Hughes et al., 2014).
Moreover, neurodegenerative diseases typically target the
ageing brain, and healthy ageing itself affects multiple stages
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
Figure 2 The auditory brain in health and neurodegenerative disease. (A) Major anatomical regions that mediate the processes under-
Hearing and dementia: from ears to brain
BRAIN 2021: 144; 391–401
| 395
Table 1 Auditory phenotypes of some major dementia syndromes
Syndrome
Core clinical
features
Alzheimer’s disease
Typical
Episodic/topographical
memory loss, parietal deficits
Auditory deficitsa
Proposed auditory
diagnostic testb
Pathological
neuroanatomyc
Difficulty tracking
sound sources/information in busy
acoustic environments, auditory disorientation, difficulty
understanding less familiar accents, auditory agnosia,
increased sound
sensitivity
Similar or more severe
than typical AD
Scene analysis, localization, attention, melody contour, accents,
environmental sound
recognition, working
memory
Auditory stream separation, sound localization/motion detectioni, DLT1,2,3,4
Posterior cingulate,
precuneus, lateral
temporo-parietal
cortex
More severe involvement of auditory
scene /spatial
processing
Phoneme perception,
prosody perception,
working memory
Pure tone detection,
complex tone perception, auditory
scene analysis,
rhythm perception,
speech loudness
perception
Auditory stream separation, sound localization/motion
detectioni,j,2,5 j
Phoneme
discriminationj,6
Sinewave speech
comprehensionk,7,8
Cortico-subcortical
circuits
Pure tone detection,
perception of pitch
interval/timbre/
rhythm/prosody, accent comprehension
Environmental sound/
voice recognition,
emotional recognition/reactivity, hedonic valuation,
integration of semantic/affective
information
Emotional recognition/
reactivity, hedonic
valuation, voice recognitionf, integration
of semantic/affective
information
Temporal pattern
discrimination9
Peri-Sylvian networks,
prefrontal cortex
Environmental sound
recognition10
Auditory/multimodal
association cortex
in anterior temporal lobe, orbitofrontal cortex,
insula
Vocal emotion
recognition11
Auditory/multimodal
association cortex
in anterior temporal lobe, orbitofrontal cortex,
insula, anterior cingulate, striatal
circuits
PCAd
Visuo-perceptual/visuospatial, other parietal
deficits
LPAd
Anomia, phonological
and verbal working
memory deficits
Fluctuating alertness/attention/executive
deficits, visuo-perceptual deficits, visual
hallucinations, REM
sleep behaviour disorder, parkinsonism
Similar or more severe
than typical AD
Speech production deficits, agrammatism
Agnosia for environmental sounds/
accents, word
deafnessf
svPPA
Anomia and vocabulary
loss, visual agnosias,
behavioural changes
similar to bvFTD
Musicophilia/sound
aversiong, tinnitus,
phonagnosia/nonverbal sound agnosia
bvFTD
Socio-emotional, executive dysfunction
with disinhibition, apathy, loss of empathy,
obsessions and rituals, dietary and
other behavioural
abnormalities
Sound aversion/musicophiliag, phonagnosiah
LBDe
FTD
nfvPPA
Auditory hallucinations
The table summarizes major clinical features, and auditory cognitive deficits, candidate auditory cognitive tests for early diagnosis and neuroanatomical associations in canonical dementia syndromes for which adequate data are available (see also Fig. 3).
a
Auditory domains affected based on behavioural test performance; bBased currently on experimental studies (examples referenced below) with a view (particularly for
Alzheimer’s disease) to potential scalability, e.g. online administration, but provisional and require further clinical validation; cMajor distribution of pathological changes in brain networks relevant to auditory deficits, as assessed using voxel-based morphometry, functional neuroimaging (chiefly functional MRI) and/or post-mortem material; dUnderpinned by
Alzheimer pathology in majority of cases; eIncludes dementia with Lewy bodies and Parkinson’s disease dementia; fNot usually severe; gAssociated with altered autonomic responses
to sound; hParticularly associated with right temporal lobe atrophy; iCan be delivered via headphones using virtual space stimuli; jOther auditory abnormalities analogous to typical
Alzheimer’s disease; kProcessing of degraded (e.g. sinewave-transformed) speech that is subject to perceptual learning and modulated by neurotransmitter function, by analogy with
tests on degraded visual stimuli that show promise for diagnosis of LBD.
AD = Alzheimer’s disease; bvFTD = behavioural variant frontotemporal dementia; DLT = dichotic listening test; FTD = frontotemporal dementia; LBD = Lewy body disease;
LPA = logopenic aphasia; nfvPPA = non-fluent agrammatic variant of progressive non-fluent aphasia; PCA = posterior cortical atrophy; svPPA = semantic variant of primary progressive aphasia.
Examples of experimental studies using proposed tests: 1Goll et al., 2012a; 2Golden et al., 2015c; 3Tuwaig et al., 2017; 4Gates et al., 2011; 5Hardy et al., 2020; 6Johnson et al., 2020;
7
Weil et al., 2017; 8Hardy et al., 2017c; 9Grube et al., 2016; 10Golden et al., 2015b; 11Omar et al., 2011.
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
Key auditory
symptoms
396
| BRAIN 2021: 144; 391–401
J. C. S. Johnson et al.
of auditory processing, ranging from cochlea to cortex
(Bendixen, 2014; Bidelman et al., 2014; Roth, 2015; Henry
et al., 2017; Zhao et al., 2019). Some of these effects (in particular, degeneration of synapses between inner hair cells
and auditory nerve fibres) are undetectable or ‘hidden’ on
standard PTA and may therefore be underestimated (Wu
et al., 2019); other effects (such as attentional suppression of
irrelevant sensory information) may only emerge under challenging listening conditions or for particular tasks, such as
tracking fine-grained temporal information in speech
(Henry et al., 2017). Increased cognitive effort and engagement of task-relevant capacities (in auditory cortex or executive control systems) may compensate to a degree for the
widespread effects of ageing on auditory signal processing
(Profant et al., 2015; Meister et al., 2016; Glick and
Sharma, 2017; Bidelman et al., 2019); however, if compensatory mechanisms are compromised by neurodegenerative
pathology, this ‘double hit’ may cause hearing loss to become functionally significant. Such decompensation would
be relatively more likely under adverse listening conditions.
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
Figure 3 A pathophysiological synthesis of hearing impairment and dementia. This figure schematizes proposed relations between
development of peripheral hearing loss (blue), changes in auditory cognition (gold) and general cognitive function (red) and underlying neurodegeneration (black), based on emerging epidemiological and pathophysiological evidence. Hearing loss can be considered a potential causal risk factor for cognitive decline (Risk), a proximity marker for incipient dementia (Proximity) or a feature of the established dementia syndrome
(Phenotype), according to the time window in which it occurs; the mechanisms of these effects are distinct but likely to be interdependent.
Alzheimer’s disease has been the major focus of epidemiological studies assessing the risk of developing dementia in association with hearing loss
(Lin et al., 2011; Taljaard et al., 2016; Livingston et al., 2017; Loughrey et al., 2018), though the distinction from cerebrovascular and other pathologies is problematic; midlife hearing loss may account for 10% of all cases of dementia, and has been proposed to have a direct potentiating effect
(arrow) on the evolution of neurodegeneration. Though the mechanism of this linkage is unclear, animal models suggest it could occur via cellular
effects such as oxidative stress or altered gene expression (Frenzilli et al., 2017; Park et al., 2018), changes in neural circuit function (Oxtoby et al.,
2017; Bidelman et al., 2019) or a complex interaction between aberrant circuit activity and protein spread (Griffiths et al., 2020). However, a direct causal effect has not been established: for example, peripheral hearing function was not associated with brain amyloid deposition (a relatively
specific preclinical marker of Alzheimer’s disease) in a large cohort of cognitively healthy older people (Parker et al., 2020) and such an effect
would still not account for the majority of cases of dementia with hearing alterations. Here we suggest that alterations in ‘central’ hearing or auditory cognition may constitute an early warning signal of incipient dementia, due to the computational demands imposed by listening in challenging
everyday acoustic environments. In support of this idea, predominantly central auditory deficits (involving, for example, dichotic listening) have
been shown to predict CSF tau levels and regional atrophy profiles consistent with Alzheimer’s disease pathology in cross-sectional studies
(Tuwaig et al., 2017) and longitudinal development of a clinical syndrome compatible with Alzheimer’s disease (Gates et al., 2011), while large genetic and neuropathological surveys have suggested changes in hearing (in particular, speech-in-noise perception) may be a preclinical marker of
neurodegeneration (Brenowitz et al., 2020a, b). We emphasize that deficits of peripheral and central hearing and more general cognitive functions
are likely to interact strongly, with ‘vicious cycling’.
Hearing and dementia: from ears to brain
In this context, neurodegenerative effects on auditory brain
function might act as ‘proximity makers’ for incipient, more
generalized cognitive decline.
Major dementias have
diverse auditory phenotypes
Alzheimer’s disease
Alzheimer’s disease produces a core impairment of auditory
scene analysis, not attributable to more elementary deficits
of sound perception or generic cognitive capacities
(Idrizbegovic et al., 2011). Auditory scene processing deficits
may predate onset of more generalized cognitive decline in
people at risk of developing Alzheimer’s disease (Golob
et al., 2009; Gates et al., 2011) and in both the typical
amnestic and posterior cortical (visuospatial) syndromic presentations of Alzheimer’s disease (Goll et al., 2012a; Golden
et al., 2015c; Hardy et al., 2020), suggesting that such
deficits are a functional marker of Alzheimer’s disease pathology. This interpretation would corroborate neuroanatomical findings linking impaired auditory scene analysis to
dysfunction and atrophy of the temporo-parietal ‘default
mode’ network that is essential to Alzheimer’s disease pathogenesis (Warren et al., 2012; Goll et al., 2012a; Golden
et al., 2015a, c) (Fig. 2).
More generally, auditory phenotypic features of
Alzheimer’s disease may signify a unifying deficit in encoding sound sources and patterns as distinct auditory objects
(Griffiths and Warren, 2004; Goll et al., 2010b, 2011;
Hailstone et al., 2012; Hardy et al., 2017b). Such a deficit
might ultimately underpin environmental sound agnosia in
Alzheimer’s disease (Coebergh et al., 2020) and impaired
phonological processing (most saliently in the logopenic variant) (Johnson et al., 2020), amplified by abnormalities of
auditory working memory (Dhanjal et al., 2013).
Lewy body disease
Auditory dysfunction is prevalent in the Lewy body disease
(LBD) spectrum (Parkinson’s disease and dementia with
Lewy bodies) and may be a marker of disease onset, evolution and severity (Seifan et al., 2019; Jafari et al., 2020).
Diverse auditory phenomena have been reported, ranging
from auditory hallucinations to impairments of auditory
scene analysis, tone and rhythm processing (Mollaei et al.,
2019; Cochen De Cock et al., 2020; Jafari et al., 2020).
Electrophysiologically, there is evidence of impaired auditory
| 397
startle, deviance detection, habituation and sensory filtering
(Perriol, 2005; Jafari et al., 2020) as well as olivocochlear efferent pathway dysfunction (De Keyser et al., 2019). The
unifying deficit may be dynamic disruption of synaptic transmission at multiple levels of the auditory hierarchy (Jafari
et al., 2020), due to abnormal top-down, neuromodulatory
(principally dopaminergic) regulation.
Frontotemporal dementias
Auditory perceptual dysfunction is emerging as a core feature of nfvPPA (Goll et al., 2010a, 2011; Golden et al.,
2016; Grube et al., 2016; Hardy et al., 2019), including deficits of rhythm, pitch and timbre perception (Goll et al.,
2010a, 2011; Grube et al., 2016) and sound detection
(Hardy et al., 2019). The key mechanism is likely to be
impaired auditory pattern analysis in peri-Sylvian and connected prefrontal regions that govern expectations about incoming sensory traffic (Cope et al., 2017; Hardy et al.,
2017a, b) (Fig. 2).
In contrast, semantic variant PPA typically spares elementary auditory pattern perception, leading instead to degraded
semantic analysis of environmental sounds, voices and affective auditory signals (Bozeat et al., 2000; Goll et al.,
2010a, b, 2012b; Hailstone et al., 2011; Fletcher et al.,
2015; Golden et al., 2015b; Muhammed et al., 2018). This
profile reflects selective degeneration and functional reorganization of antero-medial temporal lobe (Fig. 2) and its connections, including orbitofrontal cortices and auditory
thalamus.
In the behavioural variant of frontotemporal dementia, inappropriate emotional reactions to voices, environmental
sounds and music are often prominent (Omar et al., 2011;
Fletcher et al., 2015): these are likely to be driven by
impaired valuation and regularity decoding in complex auditory environments, linked to dysfunction of neural circuits
mediating reward and rule processing (Clark et al., 2017,
2018).
Hearing impairment: cause,
canary or corollary of
dementia?
The complex pathophysiological relations between hearing
impairment and dementia (schematized in Fig. 3) remain to
be fully defined. Impoverished sensory fidelity due to peripheral hearing loss or disturbed subcortical auditory trafficking
will potentially have effects both on auditory cognition and
more general cognitive functions such as attention, executive
processing and perceptual learning (Loughrey et al., 2018;
Fig. 1), leading to ‘vicious cycling’. Hearing loss might therefore produce both syndromic and generic cognitive signatures. The balance of these is likely to depend on stimulus
and task demands as well as the particular neurodegenerative process. Emerging epidemiological evidence suggests
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
The neurodegenerative diseases that cause canonical dementia syndromes have specific profiles of large-scale, corticosubcortical network involvement, determined by the patterns
of spread of pathogenic proteins (Seeley et al., 2009; Warren
et al., 2013) (examples in Fig. 2). These pathologies have
correspondingly diverse clinical phenotypes including prominent auditory cognitive deficits (Table 1).
BRAIN 2021: 144; 391–401
398
| BRAIN 2021: 144; 391–401
that hearing impairment may potentiate neurodegeneration,
perhaps via an interaction of aberrant auditory activity with
culprit proteinopathies in vulnerable neural circuits (Griffiths
et al., 2020) (Fig. 3). Indeed, hearing impairment might constitute a facilitating cause of neurodegenerative disease evolution, an early warning ‘canary’ for impending cognitive
disaster or an accompaniment of established dementia: these
non-exclusive mechanisms would have mutually reinforcing
consequences for auditory brain function.
The balance of neuroanatomical, physiological and clinical
evidence suggests that the auditory brain plays a key role in
the increasingly well documented association between dementia and hearing impairment. Degeneration of central
auditory processing mechanisms (in particular, auditory cognitive dysfunction) will tend to amplify any degree of peripheral deafness and reduce compensatory capacity under
natural (noisy) listening conditions. This reflects the extensive reciprocal interplay between afferent and efferent auditory processing pathways, exquisitely vulnerable to
neurodegenerative proteinopathies. Moreover, neurodegenerative pathologies have distinct and relatively specific
auditory cognitive phenotypes as well as generic effects on
cognitive functions relevant to hearing, in line with the
large-scale neural network signatures of these diseases. The
synthesis we propose has neurobiological, diagnostic and
management implications that should be tackled in future
work.
Neurobiologically, central auditory dysfunction is likely to
be a fundamental, early consequence of neurodegenerative
dementias, due both to direct involvement of susceptible
auditory processing networks by pathogenic protein spread
and remote effects on highly interconnected structures. This
requires substantiation using physiologically grounded neuroimaging techniques such as functional MRI and magnetoencephalography that may also help clarify the neural
mechanisms of compensatory and therapeutic effects.
Detailed, longitudinal disease phenotyping with biomarker
and ultimately histopathological support (accounting for
healthy auditory ageing and comorbid disease) will be
required to elucidate the auditory pathophysiological signatures of particular proteinopathies, to assess the relative importance of hearing impairment in different diseases and to
clarify the role of peripheral hearing deficits in potentiating
the neurodegenerative process (Griffiths et al., 2020).
Diagnostically, hearing impairment might plausibly constitute a proximity marker for incipient cognitive decline and
dementia, reflecting the heavy computational demands that
auditory signal processing imposes on failing neural circuits.
If substantiated in longitudinal studies of at-risk populations,
this would raise the exciting prospect of novel auditory ‘cognitive stress tests’ for detecting the early stages of
neurodegeneration and identifying dynamic, physiological
biomarkers of disease evolution, residual plasticity and
therapeutic response (Hardy et al., 2018). Such markers
could represent red flags for targeting population-based
screening and recruitment into dementia prevention trials
from primary care settings and could be developed into
‘digital biomarkers’ that are highly scalable. For example,
headphone-based tests of spatial hearing, degraded speech
perception and dichotic listening could be performed online
(Gates et al., 2011; Golden et al., 2015c). In addition, developing a toolkit of novel tests to quantify the relative contributions of peripheral and central auditory deficits would
allow accurate characterization of auditory phenotypes in individual patients and could facilitate diagnosis of particular
neurodegenerative pathologies (Table 1). It will be crucial to
capture the real-world impact of central hearing impairment,
which is likely to be more profound than would be predicted
by the degree of any peripheral hearing loss.
Management approaches that focus solely on peripheral
sound amplification are likely to be of limited efficacy for
improving hearing function in dementia. There is a clear
practical and pathophysiological motivation to address any
potentially reversible component of peripheral hearing loss
and ensuring compliance with hearing aids (Proctor et al.,
2020). Ultimately, however, the goal of management should
be to minimize hearing-related disability in the complex listening environments of daily life—to treat the patient, not
the audiogram or the neuropsychological test score.
Personalized interventions directed to central auditory mechanisms such as ‘smart’ hearing aids (Koohi et al., 2017),
hearing-based behavioural therapies and auditory cognitive
rehabilitation (Russo et al., 2005) should be combined with
education and environmental modification supported by a
detailed assessment of functional disability. Pharmacological
modulation of cholinergic and dopaminergic function to harness auditory plasticity has shown early promise in
Alzheimer’s disease and LBD (Dhanjal et al., 2013; Hardy
et al., 2017c; Jafari et al., 2020): such approaches could herald a new era of physiologically informed, integrated management focusing on retained capacity rather than deficits
and embracing both central and peripheral auditory impairment in dementia.
Funding
The Dementia Research Centre is supported by Alzheimer’s
Research UK, Brain Research Trust, and The Wolfson
Foundation. This work was supported by the Alzheimer’s
Society, Alzheimer’s Research UK and the National Institute
for Health Research University College London Hospitals
Biomedical Research Centre. J.C.S.J. is supported by an
Association of British Neurologists Clinical Research
Training Fellowship, funded by Guarantors of Brain.
C.R.M. is supported by a grant from Bart’s Charity. R.S.W.
is supported by a Wellcome Clinical Research Career
Development Fellowship (201567/Z/16/Z). D.E.B. is
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
Conclusions: a synthesis and
future view
J. C. S. Johnson et al.
Hearing and dementia: from ears to brain
supported by a BRC Hearing and Deafness grant. C.J.D.H.
is supported by an Action on Hearing Loss-Dunhill Medical
Trust Pauline Ashley Fellowship. J.D.W. receives grant support from Action on Hearing Loss, Alzheimer’s Research
UK, Alzheimer’s Society, Guarantors of Brain, Brain
Research UK, MRC, Wellcome Trust, and the Wolfson
Foundation.
Competing interests
The authors report no competing interests.
Anderson S, Parbery-Clark A, Yi H-G, Kraus N. A neural basis of
speech-in-noise perception in older adults. Ear Heart 2011; 32:
750–7.
Barascud N, Pearce MT, Griffiths TD, Friston KJ, Chait M. Brain
responses in humans reveal ideal observer-like sensitivity to complex
acoustic patterns. Proc Natl Acad Sci USA 2016; 113: E616–25.
Bendixen A. Predictability effects in auditory scene analysis: a review.
Front Neurosci 2014; 8: 60.
Bidelman GM, Lowther JE, Tak SH, Alain C. Mild cognitive impairment is characterized by deficient brainstem and cortical representations of speech. J Neurosci 2017; 37: 3610–20.
Bidelman GM, Mahmud MS, Yeasin M, Shen D, Arnott SR, Alain C.
Age-related hearing loss increases full-brain connectivity while
reversing directed signaling within the dorsal–ventral pathway for
speech. Brain Struct Funct 2019; 224: 2661–76.
Bidelman GM, Villafuerte JW, Moreno S, Alain C. Age-related
changes in the subcortical-cortical encoding and categorical perception of speech. Neurobiol Aging 2014; 35: 2526–40.
Bizley JK, Walker KMM, Silverman BW, King AJ, Schnupp JWH.
Interdependent encoding of pitch, timbre, and spatial location in
auditory cortex. J Neurosci 2009; 29: 2064–75.
Bozeat S, Lambon Ralph MA, Patterson K, Garrard P, Hodges JR.
Non-verbal semantic impairment in semantic dementia.
Neuropsychologia 2000; 38: 1207–15.
Brenowitz WD, Besser LM, Kukull WA, Keene CD, Glymour MM,
Yaffe K. Clinician-judged hearing impairment and associations with
neuropathologic burden. Neurology 2020; 95: e1640–9.
Brenowitz WD, Filshtein TJ, Yaffe K, Walter S, Ackley SF, Hoffmann
TJ, et al. Association of genetic risk for Alzheimer disease and hearing impairment. Neurology 2020; 95: e2225.
Clark CN, Golden HL, McCallion O, Nicholas JM, Cohen MH, Slattery
CF, et al. Music models aberrant rule decoding and reward valuation
in dementia. Soc Cogn Affect Neurosci 2018; 13: 192–202.
Clark CN, Nicholas JM, Agustus JL, Hardy CJD, Russell LL,
Brotherhood EV, et al. Auditory conflict and congruence in frontotemporal dementia. Neuropsychologia 2017; 104: 144–56.
Cochen De Cock V, Verbizier D, Picot MC, Damm L, Abril B, Galtier
F, et al. Rhythm disturbances as a potential early marker of
Parkinson’s disease in idiopathic REM sleep behavior disorder. Ann
Clin Transl Neurol 2020; 7: 280–7.
Coebergh JAF, McDowell S, van Woerkom TCAM, Koopman JP,
Mulder J, Bruijn SFTM. Auditory agnosia for environmental sounds
in Alzheimer’s disease: not hearing and not listening? J Alzheimers
Dis 2020; 73: 1407–19.
Cope TE, Baguley DM, Griffiths TD. The functional anatomy of central auditory processing. Pract Neurol 2015; 15: 302–8.
Cope TE, Sohoglu E, Sedley W, Patterson K, Jones PS, Wiggins J,
et al. Evidence for causal top-down frontal contributions to predictive processes in speech perception. Nat Commun 2017; 8: 2154.
| 399
Dawes P, Emsley R, Cruickshanks KJ, Moore DR, Fortnum H,
Edmondson-Jones M, et al. Hearing loss and cognition: the role of
hearing AIDS, social isolation and depression. PLoS One 2015; 10:
e0119616.
De Keyser K, De Letter M, De Groote E, Santens P, Talsma D,
Botteldooren D, et al. Systematic audiological assessment of auditory
functioning in patients with Parkinson’s disease. J Speech Lang
Heart Res 2019; 62: 4564–77.
Dhanjal NS, Warren JE, Patel MC, Wise RJS. Auditory cortical function during verbal episodic memory encoding in Alzheimer’s disease.
Ann Neurol 2013; 73: 294–302.
Donhauser PW, Baillet S. Two distinct neural timescales for predictive
speech processing. Neuron 2020; 105: 385–93.e9.
Esiri MM, Pearson RCA, Powell TPS. The cortex of the primary auditory area in Alzheimer’s disease. Brain Res 1986; 366: 385–7.
Eversfield CL, Orton LD. Auditory and visual hallucination prevalence
in Parkinson’s disease and dementia with Lewy bodies: a systematic
review and meta-analysis. Psychol Med 2019; 49: 2342–53.
Fletcher PD, Downey LE, Golden HL, Clark CN, Slattery CF,
Paterson RW, et al. Auditory hedonic phenotypes in dementia: a
behavioural and neuroanatomical analysis. Cortex 2015; 67:
95–105.
Frenzilli G, Ryskalin L, Ferrucci M, Cantafora E, Chelazzi S, Giorgi
FS, et al. Loud noise exposure produces dna, neurotransmitter and
morphological damage within specific brain areas. Front Neuroanat
2017; 11: 49.
Gates G, Mills J. Presbycusis. Lancet 2005; 366: 1111–20.
Gates GA, Anderson ML, McCurry SM, Feeney MP, Larson EB.
Central auditory dysfunction as a harbinger of Alzheimer dementia.
Arch Otolaryngol Head Neck Surg 2011; 137: 390.
Gates GA, Gibbons LE, McCurry SM, McCusrry SM, Crane PK,
Feeney MP, et al. Executive dysfunction and presbycusis in older
persons with and without memory loss and dementia. Cogn Behav
Neurol 2010; 23: 218–23.
Gaucher Q, Huetz C, Gourévitch B, Laudanski J, Occelli F, Edeline
JM. How do auditory cortex neurons represent communication
sounds? Heart Res 2013; 305: 102–12.
Glick H, Sharma A. Cross-modal plasticity in developmental and agerelated hearing loss: clinical implications. Heart Res 2017; 343:
191–201.
Golden HL, Agustus JL, Goll JC, Downey LE, Mummery CJ, Schott
JM, et al. Functional neuroanatomy of auditory scene analysis in
Alzheimer’s disease. NeuroImage Clin 2015a; 7: 699–708.
Golden HL, Clark CN, Nicholas JM, Cohen MH, Slattery CF,
Paterson RW, et al. Music perception in dementia. J Alzheimers Dis
2016; 55: 933–49.
Golden HL, Downey LE, Fletcher PD, Mahoney CJ, Schott JM,
Mummery CJ, et al. Identification of environmental sounds and melodies in syndromes of anterior temporal lobe degeneration. J Neurol
Sci 2015b; 352: 94–8.
Golden HL, Nicholas JM, Yong KXX, Downey LE, Schott JM,
Mummery CJ, et al. Auditory spatial processing in Alzheimer’s disease. Brain 2015c; 138: 189–202.
Goll JC, Crutch SJ, Loo JHY, Rohrer JD, Frost C, Bamiou DE, et al.
Non-verbal sound processing in the primary progressive aphasias.
Brain 2010a; 133: 272–85.
Goll JC, Crutch SJ, Warren JD. Central auditory disorders: toward a
neuropsychology of auditory objects. Curr Opin Neurol 2010b; 23:
617–27.
Goll JC, Kim LG, Hailstone JC, Lehmann M, Buckley A, Crutch SJ, et al.
Auditory object cognition in dementia. Neuropsychologia 2011; 49:
2755–65.
Goll JC, Kim LG, Ridgway GR, Hailstone JC, Lehmann M, Buckley
AH, et al. Impairments of auditory scene analysis in Alzheimer’s disease. Brain 2012a; 135: 190–200.
Goll JC, Ridgway GR, Crutch SJ, Theunissen FE, Warren JD.
Nonverbal sound processing in semantic dementia: a functional
MRI study. Neuroimage 2012b; 61: 170–80.
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
References
BRAIN 2021: 144; 391–401
400
| BRAIN 2021: 144; 391–401
disease and in mild cognitive impairment. Age Ageing 2011; 40:
249–54.
Jafari Z, Kolb BE, Mohajerani MH. Auditory dysfunction in
Parkinson’s disease. Mov Disord 2020; 35: 537–50.
Johnson JCS, Jiang J, Bond RL, Benhamou E, Requena-Komuro M,
Russell LL, et al. Impaired phonemic discrimination in logopenic
variant primary progressive aphasia. Ann Clin Transl Neurol 2020;
7: 1252–7.
King AJ, Nelken I. Unraveling the principles of auditory cortical processing: can we learn from the visual system? Nat Neurosci 2009; 12:
698–701.
Koohi N, Vickers D, Warren J, Werring D, Bamiou D-E. Long-term
use benefits of personal frequency-modulated systems for speech in
noise perception in patients with stroke with auditory processing
deficits: a non-randomised controlled trial study. BMJ Open 2017;
7: e013003.
Kuchibhotla KV, Gill JV, Lindsay GW, Papadoyannis ES, Field RE,
Sten TAH, et al. Parallel processing by cortical inhibition enables
context-dependent behavior. Nat Neurosci 2017; 20: 62–71.
Kurylo DD, Corkin S, Allard T, Zatorre RJ, Growdon JH. Auditory
function in Alzheimer’s disease. Neurology 1993; 43: 1893.
Lewis D, Campbell M, Terry R, Morrison J. Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in
Alzheimer’s disease: a quantitative study of visual and auditory cortices. J Neurosci 1987; 7: 1799–808.
Lin FB, Metter J, O’Brien R, Resnick SM, Zonderman AB, Ferrucci L,
et al. Hearing loss and incident dementia. Johns Hopkins Med
2011; 68: 214–20.
Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J,
Ames D, et al. Dementia prevention, intervention, and care. Lancet
2017; 390: 2673–734.
Loughrey DG, Kelly ME, Kelley GA, Brennan S, Lawlor BA. Association
of age-related hearing loss with cognitive function, cognitive impairment, and dementia a systematic review and meta-analysis. JAMA
Otolaryngol Head Neck Surg 2018; 144: 115–26.
Mahoney CJ, Rohrer JD, Goll JC, Fox NC, Rossor MN, Warren JD.
Structural neuroanatomy of tinnitus and hyperacusis in semantic dementia. J Neurol Neurosurg Psychiatry 2011; 82: 1274–8.
Malmierca MS, Sanchez-Vives MV, Escera C, Bendixen A. Neuronal
adaptation, novelty detection and regularity encoding in audition.
Front Syst Neurosci 2014; 8: 111.
Meister H, Schreitmüller S, Ortmann M, Rählmann S, Walger M.
Effects of hearing loss and cognitive load on speech recognition with
competing talkers. Front Psychol 2016; 7: 301.
Minces V, Pinto L, Dan Y, Chiba AA. Cholinergic shaping of neural
correlations. Proc Natl Acad Sci USA 2017; 114: 5725–30.
Mollaei F, Shiller DM, Baum SR, Gracco VL. The relationship between speech perceptual discrimination and speech production in
Parkinson’s disease. J Speech Lang Heart Res 2019; 62: 4256–68.
Muhammed L, Hardy CJD, Russell LL, Marshall CR, Clark CN,
Bond RL, et al. Agnosia for bird calls. Neuropsychologia 2018; 113:
61–7.
Musiek FE, Shinn J, Chermak GD, Bamiou D-E. Perspectives on the
pure-tone audiogram. J Am Acad Audiol 2017; 28: 655–71.
Omar R, Henley SMD, Bartlett JW, Hailstone JC, Gordon E, Sauter
DA, et al. The structural neuroanatomy of music emotion recognition: evidence from frontotemporal lobar degeneration. Neuroimage
2011; 56: 1814–21.
Oxtoby NP, Garbarino S, Firth NC, Warren JD, Schott JM, Alexander
DC. Data-driven sequence of changes to anatomical brain connectivity in sporadic Alzheimer’s disease. Front Neurol 2017; 8: 580.
Panza F, Solfrizzi V, Seripa D, Imbimbo BP, Capozzo R, Quaranta N,
et al. Age-related hearing impairment and frailty in Alzheimer’s disease: interconnected associations and mechanisms. Front Aging
Neurosci 2015; 7: 2020–28.
Park SY, Kim MJ, Kim HL, Kim DK, Yeo SW, Park SN. Cognitive decline and increased hippocampal p-tau expression in mice with hearing loss. Behav Brain Res 2018; 342: 19–26.
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
Golob EJ, Ringman JM, Irimajiri R, Bright S, Schaffer B, Medina LD,
et al. Cortical event-related potentials in preclinical familial
Alzheimer disease. Neurology 2009; 73: 1649–55.
Graydon K, Waterworth C, Miller H, Gunasekera H. Global burden
of hearing impairment and ear disease. J Laryngol Otol 2019; 133:
18–25.
Griffiths TD, Lad M, Kumar S, Holmes E, McMurray B, Maguire EA,
et al. How can hearing loss cause dementia? Neuron 2020; 108:
401–12.
Griffiths TD, Uppenkamp S, Johnsrude I, Josephs O, Patterson RD.
Encoding of the temporal regularity of sound in the human brainstem. Nat Neurosci 2001; 4: 633–7.
Griffiths TD, Warren JD. What is an auditory object? Nat Rev
Neurosci 2004; 5: 887–92.
Grube M, Bruffaerts R, Schaeverbeke J, Neyens V, De Weer AS,
Seghers A, et al. Core auditory processing deficits in primary progressive aphasia. Brain 2016; 139: 1817–29.
Guest H, Munro KJ, Prendergast G, Millman RE, Plack CJ. Impaired
speech perception in noise with a normal audiogram: no evidence
for cochlear synaptopathy and no relation to lifetime noise exposure. Heart Res 2018; 364: 142–51.
Guinan JJ. Olivocochlear efferents: their action, effects, measurement
and uses, and the impact of the new conception of cochlear mechanical responses. Heart Res 2018; 362: 38–47.
Hailstone JC, Ridgway GR, Bartlett JW, Goll JC, Buckley AH, Crutch
SJ, et al. Voice processing in dementia: a neuropsychological and
neuroanatomical analysis. Brain 2011; 134: 2535–47.
Hailstone JC, Ridgway GR, Bartlett JW, Goll JC, Crutch SJ, Warren
JD. Accent processing in dementia. Neuropsychologia 2012; 50:
2233–44.
Hardy CJD, Agustus JL, Marshall CR, Clark CN, Russell LL, Bond
RL, et al. Behavioural and neuroanatomical correlates of auditory
speech analysis in primary progressive aphasias. Alzheimers Res
Ther 2017a; 9: 53.
Hardy CJD, Agustus JL, Marshall CR, Clark CN, Russell LL,
Brotherhood EV, et al. Functional neuroanatomy of speech signal
decoding in primary progressive aphasias. Neurobiol Aging 2017b;
56: 190–201.
Hardy CJD, Frost C, Sivasathiaseelan H, Johnson JCS, Agustus JL,
Bond RL, et al. Findings of impaired hearing in patients with nonfluent/agrammatic variant primary progressive aphasia. JAMA Neurol
2019; 76: 607.
Hardy CJD, Hwang YT, Bond RL, Marshall CR, Ridha BH, Crutch
SJ, et al. Donepezil enhances understanding of degraded
speech in Alzheimer’s disease. Ann Clin Transl Neurol 2017c; 4:
835–40.
Hardy CJD, Marshall CR, Bond RL, Russell LL, Dick K, Ariti C, et al.
Retained capacity for perceptual learning of degraded speech in primary progressive aphasia and Alzheimer’s disease. Alzheimers Res
Ther 2018; 10: 70.
Hardy CJD, Marshall CR, Golden HL, Clark CN, Mummery CJ,
Griffiths TD, et al. Hearing and dementia. J Neurol 2016; 263:
2339–54.
Hardy CJD, Yong KXX, Goll JC, Crutch SJ, Warren JD. Impairments
of auditory scene analysis in posterior cortical atrophy. Brain 2020;
143: 2689–95.
Henry MJ, Herrmann B, Kunke D, Obleser J. Aging affects the balance
of neural entrainment and top-down neural modulation in the listening brain. Nat Commun 2017; 8: 15801.
Holmes E, Griffiths TD. ‘Normal’ hearing thresholds and fundamental
auditory grouping processes predict difficulties with speech-in-noise
perception. Sci Rep 2019; 9: 16771.
Hughes LE, Rowe JB, Ghosh BCP, Carlyon RP, Plack CJ, Gockel HE.
The binaural masking level difference: cortical correlates persist despite severe brain stem atrophy in progressive supranuclear palsy.
J Neurophysiol 2014; 112: 3086–94.
Idrizbegovic E, Hederstierna C, Dahlquist M, Kampfe Nordstrom C,
Jelic V, Rosenhall U. Central auditory function in early Alzheimer’s
J. C. S. Johnson et al.
Hearing and dementia: from ears to brain
| 401
Strouse AL, Hall JW, Burger MC. Central auditory processing in
Alzheimer’s disease. Ear Heart 1995; 16: 230–8.
Taljaard DS, Olaithe M, Brennan-Jones CG, Eikelboom RH, Bucks
RS. The relationship between hearing impairment and cognitive
function: a meta-analysis in adults. Clin Otolaryngol 2016; 41:
718–29.
Terreros G, Delano PH. Corticofugal modulation of peripheral auditory responses. Front Syst Neurosci 2015; 9: 2019–30.
Tuwaig M, Savard M, Jutras B, Poirier J, Collins DL, Rosa-Neto P;
for the PREVENT-AD Research Group, et al. Deficit in central auditory processing as a biomarker of pre-clinical Alzheimer’s disease. J
Alzheimers Dis 2017; 60: 1589–600.
Wang X. Neural coding strategies in auditory cortex. Heart Res 2007;
229: 81–93.
Warren JD, Fletcher PD, Golden HL. The paradox of syndromic diversity in Alzheimer disease. Nat Rev Neurol 2012; 8: 451–64.
Warren JD, Rohrer JD, Schott JM, Fox NC, Hardy J, Rossor MN.
Molecular nexopathies: a new paradigm of neurodegenerative disease. Trends Neurosci 2013; 36: 561–9.
Wayne RV, Johnsrude IS. A review of causal mechanisms underlying
the link between age-related hearing loss and cognitive decline.
Ageing Res Rev 2015; 23: 154–66.
Weil RS, Pappa K, Schade RN, Schrag AE, Bahrami B, Schwarzkopf
DS, et al. The cats-and-dogs test: A tool to identify visuoperceptual
deficits in Parkinson’s disease. Mov Disord 2017; 32: 1789–90. doi:
10.1002/mds.27176.
Wu PZ, Liberman LD, Bennett K, de Gruttola V, O’Malley JT,
Liberman MC. Primary neural degeneration in the human cochlea:
evidence for hidden hearing loss in the aging ear. Neuroscience
2019; 407: 8–20.
Zhao S, Bury G, Milne A, Chait M. Pupillometry as an objective measure of sustained attention in young and older listeners. Trends Heart
2019; 23: 233121651988781.
Zion Golumbic EM, Ding N, Bickel S, Lakatos P, Schevon CA,
McKhann GM, et al. Mechanisms underlying selective neuronal
tracking of attended speech at a “cocktail party”. Neuron 2013; 77:
980–91.
Downloaded from https://academic.oup.com/brain/article/144/2/391/6044086 by guest on 22 May 2021
Parker T, Cash DM, Lane C, Lu K, Malone IB, Nicholas JM, et al.
Pure tone audiometry and cerebral pathology in healthy older
adults. J Neurol Neurosurg Psychiatry 2020; 91: 172–6.
Perriol M-P. Disturbance of sensory filtering in dementia with Lewy
bodies: comparison with Parkinson’s disease dementia and Alzheimer’s
disease. J Neurol Neurosurg Psychiatry 2005; 76: 106–8.
Pickles JO, Auditory pathways: anatomy and physiology. 1st edn.
Oxford: Elsevier B.V.; 2015.
Pressnitzer D, Sayles M, Micheyl C, Winter IM. Perceptual organization of sound begins in the auditory periphery. Curr Biol 2008; 18:
1124–8.
Proctor D, Bamiou D-E, Karia D, Lewis G, Livingston G, Omar RZ,
et al. Identifying and treating hearing loss in mild cognitive impairment: a feasibility study for an interventional trial with hearing aids.
Int Psychogeriatr 2020; 32: 537–8.
Profant O, Tintera J, Balogová Z, Ibrahim I, Jilek M, Syka J.
Functional changes in the human auditory cortex in ageing. PLoS
One 2015; 10: e0116692.
Rohrer JD, Sauter D, Scott S, Rossor MN, Warren JD. Receptive prosody in nonfluent primary progressive aphasias. Cortex 2012; 48:
308–16.
Roth TN, Aging of the auditory system. 1st edn. Oxford: Elsevier
B.V.; 2015.
Russo NM, Nicol TG, Zecker SG, Hayes EA, Kraus N. Auditory training improves neural timing in the human brainstem. Behav Brain
Res 2005; 156: 95–103.
Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD.
Neurodegenerative diseases target large-scale human brain networks.
Neuron 2009; 62: 42–52.
Seifan A, Ganzer CA, Ryon K, Lin M, Mahmudur R, Adolfo H, et al.
Detecting non-cognitive Features of Prodromal Neurodegenerative
Diseases. Cas 2019; 11: 242–9.
Shamma SA, Micheyl C. Behind the scenes of auditory perception.
Curr Opin Neurobiol 2010; 20: 361–6.
Simon JZ. The encoding of auditory objects in auditory cortex:
insights from magnetoencephalography. Int J Psychophysiol 2015;
95: 184–90.
BRAIN 2021: 144; 391–401