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6 odorants in a “scratch and sniff” test. This study
indicated that age was an important factor: decline
began in the second decade of life [39]. A study by
the NIH in collaboration with the National Center
for Health Statistics, conducted in 1993 to acquire
information on the prevalence of smell/taste problems, showed an overall prevalence of 2.7 million
(1.4%) US adults with olfactory problems.
Prevalence rates increased exponentially with age;
almost 40% of 1.5 million respondents reporting a
chemosensory problem were 65 or more years of
age [32, 40].
The ability to detect, discriminate, and identify odors is most sensitive to age- and diseaserelated dysfunction [39, 41]. And the elderly
population is increasing due to improved health
care throughout the world. Despite the widespread age-related prevalence of olfactory loss,
remarkably little is known about the specic
mechanisms responsible, and no treatments are
currently available.
The impact of sensory loss on elders is not only
physiological but also emotional. Taste and smell
are fundamental sensory systems responsible for
the perception of aroma and avor. Olfactory dysfunction can also lead to changes of dietary habits
that may in turn exacerbate disease states or contribute to nutritional deciencies [33, 37].
The susceptibility of elderly people to aging
and diseases, particularly neurodegenerative diseases, varies. Therefore, complaints about sensory functions should be seriously considered as
possible indicators of neurodegenerative disease
or another underlying condition (e.g., medication
side effects).
The composition of mucus is critical to proper
ORN function and may change with hydration,
which is often reduced in the elderly, as well as
from age-related diseases or associated medications. Changes at the level of the ORN may also
reduce and/or alter olfactory function. For
instance, age-related loss of selectivity was
observed in a study of odorant response characteristics of ORNs dissociated from biopsies [31],
and age-related changes in ion channel distribution [42, 43] or other components of the intracellular signaling cascades [44] could result in
receptor cell dysfunction.
Although the extent of olfactory epithelium is
reduced with aging [31, 45], whether this
accounts for age-related olfactory loss remains
unclear: studies indicate that olfactory function is
not affected even with substantial reduction of
olfactory epithelial area [31, 45]. Other anatomical changes, such as altered vascular and mucosal
composition and peptidergic innervation, could
lead to reduced sensitivity through indirect mechanisms or changes in the transport and clearance
of odorants [46]. Sensory dysfunction may be a
consequence of chronic disease, such as diabetes,
cancer, radiation, surgery, or dentures. However,
in most cases the cause of olfactory loss is
unknown, and the development of treatments will
require a better understanding of the mechanisms
underlying this sensory impairment.
31.3.2 Chronic Rhinosinusitis (CRS)
Many olfactory dysfunctions are related to CRS,
nasal polyps, and allergies [47]. Olfactory dysfunction is a frequent complaint in CRS patients.
CRS is an inammatory disease that occurs in the
nasal cavity and sinus mucosa [29]. In most
patients, CRS is accompanied by olfactory or
taste dysfunctions that can compromise their
quality of life. Many of patients with CRS are
known to have olfactory impairment [48, 49].
31.3.3 Neurodegenerative Diseases
Olfactory dysfunction can be the direct or indirect
result of pathological processes at any point in the
olfactory pathway. Accumulating data indicate
that neurodegenerative disorders of CNS areas
involved in olfactory processing may contribute to
olfactory dysfunction [50–52]. Nevertheless, the
precise mechanisms that connect these diseases
with olfactory loss are still unclear [53]. While
these reports suggest olfactory involvement and
potential utility in diagnostic approaches for these
diseases, no studies have been done to directly
investigate the neuropathology or cell/molecular
basis for olfactory impairment.
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A. E. Özdener-Poyraz and M. H. Özdener
Since the rst observation of olfactory function impairment in Parkinson disease [54] and
senile dementia [55], olfactory function testing
has revealed compromised olfactory function in a
number of neurodegenerative diseases, such as
Alzheimer’s disease [56–59], Parkinson disease
[60, 61], Huntington’s disease [62], HIVassociated dementia [63, 64], and amyotrophic
lateral sclerosis [65]. Using and olfactory brushing procedure to detect the pathologic prion proteins α-synuclein, β-amyloid, tau, and TDP-43in
patients with neurodegenerative disorders demonstrated the presence of proteins associated to
neurodegeneration in the cells of the olfactory
mucosa [66].
31.3.4 Alzheimer’s Disease (AD)
Olfactory impairment and neuroanatomical
changes in the central portions of the olfactory
system occur early in the development of AD,
and olfactory testing has been explored as a diagnostic aide [45, 67, 68]. Patients with AD perform more poorly on tests of odor identication
[59, 69] and exhibit altered olfactory evoked
response potentials compared to age-matched
controls [70]. Olfactory tests alone, however, are
insufcient to discriminate AD from Parkinson’s
disease, and careful consideration of cognitive
function is required to ensure reliable results
[71]. It is generally accepted that the classic AD
neuropathology occurs in the entorhinal cortex
very early in the development of the disease [72],
and this observation led some to speculate that a
causative agent might enter the brain via the nasal
epithelium.
Some have investigated whether histological
studies of biopsies of the olfactory neuroepithelium might be useful as an early diagnostic tool
for AD.However, more comprehensive studies
indicate that the density of plaques and tangles
in the olfactory bulb is less severe, and studies
of the peripheral olfactory epithelium have been
inconsistent. In general, phosphorylated tau and
neurolament proteins are not observed in the
perikarya of the olfactory neurons but are evident within the axons and dendrites of these
cells [73, 74]. Several studies have reported
AD-specic neuropathology within the olfactory epithelium [68, 75, 76], but others using
different markers have noted similar features in
non-AD and healthy olfactory tissue from
elderly controls. In addition, studies that have
included tissue from patients with other types of
dementia or neurological disease have failed to
identify any marker present in the olfactory epithelium that would serve to reliably distinguish
AD from other conditions, such as Parkinson’s
disease or vascular dementia [77, 78]. Consistent
with these ndings, while we have observed
some functional differences in preliminary studies of ORNs obtained via biopsy from patients
with early- stage AD, these neurons appeared
normal morphologically and were able to
respond to odorants [31]. Further studies of
olfactory neuronal cell function may prove more
useful than histology alone in understanding
altered cellular metabolism or signaling that
heralds the onset of AD.
31.3.5 Down’s Syndrome
Patients with Down’s syndrome display neuropathologic features similar in some respects to
those seen in AD. Likewise, individuals with
Down’s syndrome had signicant decits in
olfactory functioning compared to the control
groups [79]. The Alcohol Sniff Test, a rapid
screen for olfactory function, revealed olfactory
decits in children with Down’s syndrome [80].
Another study also indicated that olfactory decits may provide a sensitive and early indicator of
the deterioration and progression of the brain in
older patients with Down’s syndrome [81].
31.3.6 Parkinson’s Disease (PD)
Impaired olfactory function is a well-documented
abnormality in patients with PD [82]. The cellular
and molecular mechanisms for this decit are
unknown but likely relate to impairment at several
levels of the olfactory system. Olfactory impairment in PD was not related to degree of motor dys-
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function or disease duration but was related to
disease severity [61, 83–87]. Interestingly, Hawkes
etal. proposed that idiopathic PD may start in the
olfactory system prior to damage in the basal ganglia [88]. Another study indicated that olfactory
testing may be useful for differential diagnosis
between PD and progressive supranuclear palsy
(PSP) [89]. Both PD and PSP have similar motor
symptoms, and PSP is commonly misdiagnosed as
PD, although they are distinct neuropathologic
entities [31, 89].
In one study, olfactory dysfunction was
observed in patients with an abnormal reduction
in striatal dopamine transporter binding who subsequently developed clinical Parkinsonism. None
of 23 normosmic relatives of these patients developed signs or symptoms of Parkinsonism [90].
These observations indicate that olfactory decits may precede clinical motor signs in PD and
support a practical clinical application in the
early diagnosis/prognosis of the disease.
PD-related olfactory dysfunction may relate
to the function of dopamine receptors in both
central [13, 91–93] and peripheral components of
the system [13, 94–96]. Centrally, dopamine
modulates synaptic activity in the olfactory bulb
and entorhinal cortex, inuences the activity of
several ion channels and enzymes involved in
olfactory transduction, and has been reported to
induce apoptosis and modulate differentiation of
olfactory neurons in vitro [90, 97, 98]. These
effects are mediated via D2 receptors in the
periphery [98] and D1 and D2 receptors on
mitral/tufted and juxtaglomerular cells in the
olfactory bulb [99]. The dopaminergic granule
cells in the olfactory bulb derive from stem cells
that migrate from the subventricular zone
throughout life. These stem cells are being studied as a potential source for dopaminergic
replacement cells via transplant [100].
system exhibited early and signicant accumulation of huntingtin-containing aggregates,
which may account for the early olfactory
impairment [102].
31.3.8 Multiple Sclerosis
Olfactory dysfunction may also be an early indicator of disease progression in multiple sclerosis
[103]. The Cross-Cultural Smell Identication
test utilized in patients with multiple sclerosis
indicated that these patients scored signicantly
worse than control groups. They also found signicant correlations among smell alteration,
symptoms of anxiety and depression, and severity of neurological impairments [104]. In several
studies, neuropathology based on plaque numbers was directly related to olfactory function
[104, 105]: as plaque numbers declined or
increased in the inferior frontal and temporal
lobes, olfactory function declined or improved
[106–108].
31.3.9 Creutzfeldt–Jakob
Disease (CJD)
This rapidly progressive, fatal neurodegenerative
disorder is believed to be caused by pathologic
prion protein (PrPSc), which may be found in the
neuroepithelium of the olfactory mucosa in
patients with CJD [109]. Taste and smell loss
were reported as an early sign of CJD [110]. This
result indicates that olfactory biopsy may provide
diagnostic information, and further studies are
warranted.
31.3.10 Viral Infections
31.3.7 Huntington’s Disease
Patients with Huntington’s disease exhibit signicant decits in odor identication, but odor
recognition memory was not affected [67, 101].
In an animal model of the disease, the olfactory
Animal models have shown that neurotropic
viruses, such as murine coronavirus [111], Borna
disease virus [112], pseudorabies virus [113],
herpes simplex virus type 1 and 2 [114, 115],
Zika virus [116], human coronavirus OC43
[117], and adenovirus [118], reach the CNS after
having contact with the nasal mucosa. Vesicular
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stomatitis virus infects the olfactory epithelium
and then spreads along the olfactory nerves into
the glomeruli of the olfactory bulb, progressively
spreading to the brain [119]. The presence of
various viruses has been conrmed in the nasal
discharge of patients with post-viral infection
olfactory dysfunction, such as rhinovirus, parainuenza virus, Epstein-Barr virus, and coronavirus [120]. Signicant recovery was not observed
after 24weeks in almost all the patients.
31.3.11 Human Immunodeciency
Virus (HIV) Infection
andAIDS
HIV-associated dementia is a leading cause of
neurodegenerative disorders among individuals
under 30 years [121]. HIV infects the CNS;
7–25% of patients with CNS infection develop
dementia, and at least 50% of these patients
develop mild neurocognitive impairment. Several
studies have shown that patients with neurocognitive impairment caused by HIV infection had
diminished odor sensitivity [63, 64, 122].
Impaired olfactory function may serve as early
marker of HIV-associated neurological impairment [123] and could be helpful to evaluate the
impact of therapeutic agents. HIV-positive
patients had signicantly impaired menthol
detection compared to controls. It is likely that
chemosensory losses found in patients with HIV
reect both central and peripheral decits [124].
Of 207 HIV-infected patients, 70% of them
(n=144) reported that chemosensory complaints
were associated with a poor quality of life [125].
Wasting with reduced caloric intake is an increasingly common clinical manifestation of
AIDS.The perceptions of taste and smell play an
important role in stimulating caloric intake, and
avor enhancement of food can have a signicant
positive impact on nutritional status in hospitalized patients [124]. Signicant taste and smell
losses in HIV-infected patients may be of clinical
signicance in the development or progression of
HIV-associated wasting and are thus worthy of
clinical consideration and treatment [126].
31.3.12 Coronavirus-19
(SARS-CoV-19, COVID- 19)
Infection
Accumulating reports from around the world
conrm the high prevalence of different degrees
of smell and taste loss in COVID-19-positive
patients. Currently, loss of taste or smell is one
of the six most reliable symptoms of COVID19 [127]. While it is well known that coronaviruses can cause chemosensory dysfunction, the
underlying pathophysiological mechanism is
unknown and may be distinct for each chemosensory system. Since the start of the pandemic
most studies have focused specically on cellular and molecular mechanisms of coronavirus-induced smell loss.
The novel coronavirus (SARS-CoV-2) is a
highly pathogenic, Coronaviridae singlestranded, positive-sense RNA virus responsible
for the present outbreak of COVID-19. The RNA
virus genome is covered by an envelope comprising spike proteins and a lipid membrane. The
infection cycle is initiated by attachment of the
spike proteins to angiotensin-converting enzyme
2 (ACE-2), a host cell membrane protein that
serves as a receptor for viral entry by endocytosis. In addition, TMPRSS2, a 70-kDa member of
the serine protease family, becomes activated
upon proteolytic cleavage and serves as a coreceptor for the SARS-CoV-2 spike glycoprotein,
a step that facilitates virus recognition of the host
cells.
Whether and how the SARS-CoV-2 virus may
infect sensory system cells and cause olfactory
dysfunction still is a question of major interest
and concern. Sudden loss of smell and taste could
be the only features in asymptomatic newly
infected individuals and could also serve as early
symptoms of the disease. In fact, the American
Academy of Otolaryngology–Head and Neck
Surgery recognized that smell and/or taste loss
could be the only and/or early symptom of newly
infected individuals and recommended
self- isolation for anyone with these symptoms
[128]. The WHO has also recognized them as key
symptoms of COVID-19 [129, 130].
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31.3.13 Inuenza Virus Infection
Upper respiratory tract viral infections, such as
inuenza, parainuenza, and rhinovirus, are
among the most common causes of olfactory dysfunction [131]. Post-viral olfactory disorder develops after infection with the common cold and is a
relatively severe and prolonged disorder without
rhinosinusitis [132]. Changes in olfactory perception in patients with the inuenza or parainuenza
type 3 viruses have been reported. Seasonal
changes in the incidence of olfactory loss have
been reported with respect to inuenza and parainuenza type 3 infections, occurring most frequently in winter and spring, respectively [120].
31.3.14 Medications andOlfactory
Dysfunction
When assessing patients for reduced ability, complete inability, or distorted ability to smell
(hyposmia, anosmia, dysosmia/parosmia, respec-
tively), it is important to consider their medications. Because olfaction is a strong indicator for
quality of life, drug-induced olfactory changes
can also lead to medication nonadherence, which
compromises the management of acute and
chronic conditions.
Table 31.1 lists some common medications
associated with olfactory change, including antibiotics, cardiovascular drugs, decongestant nose
sprays, and intranasal zinc products. In 2009, the
US Food and Drug Administration (FDA) issued
a warning to consumers to discontinue the zinccontaining nasal spray Zicam, which was marketed to shorten the duration of the cold. The
FDA received over 100 reports from doctors and
consumers citing a causative relationship
between the zinc nasal spray and anosmia. In
some cases, this adverse drug effect was permanent [133, 134].
Most of the information available about specic drugs causing olfactory changes is from case
reports rather than from large, randomized, controlled trials. One study identied 71 drugs that
Table 31.1 Drugs associated with changes in smell [135, 136, 139, 150–156]
Drug class Drug names Effect on olfactory system
Cardiovascular
ACE inhibitors Enalapril Reduced
Calcium-channel blockers Diltiazem, amlodipine, felodipine,
nifedipine
HMGCo-A reductase
inhibitors
Alpha1 blocker Doxazosin Altered
Antiarrhythmic Tocainide, amiodarone Altered
Antibiotics
Macrolides Azithromycin, clarithromycin Reduced
Penicillin Amoxicillin Reduced
Fluoroquinolones Ciprooxacin, levooxacin Reduced
Tetracycline Doxycycline Altered
Miscellaneous
Antihistamine and
anti-allergy
Thyroid Levothyroxine Altered
Opioid analgesic Morphine Reduced
Blood viscosity reducer Pentoxifylline Enhanced
Phosphodiesterase-5 inhibitor Sildenal Reduced
Immunomodulatory Alpha interferon, methotrexate Interferon reduced, methotrexate
Antifungal Terbinane Reduced
Topical Silver nitrate Reduced
Antidepressant Duloxetine Altered
Atorvastatin, lovastatin, pravastatin Altered
Intranasal zinc, uticasone, prednisone Reduced
Reduced
enhanced
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probably alter olfaction in humans [135]. Another
study showed that long-term use of opioid and
nonopioid analgesics caused signicant reduction in olfactory function compared to agematched controls not taking analgesics [136].
Patients may develop drug-induced olfactory
disturbances for several reasons. Medications
may damage olfactory mucosa regeneration,
deplete trace metals, such as zinc, or cause neurotoxicity that impairs smell pathways. Topical silver nitrate and silver sulfadiazine are used as an
antibiotic in thermal injury. Prolonged use of
these drugs can lead to silver deposition in the
nasal mucosa, leading to anosmia. Drugs can also
cause impairment of neuronal and mucosal tissue
potassium and calcium ion efux, causing a
reduction in impulse conduction [4]. Calcium
channel blockers, such as nifedipine and diltiazem, inhibit calcium-mediated impulse transmission to the olfactory bulb, which can lead to
anosmia in some patients [137, 138]. Additional
pathways that can impact olfaction include
reduced access to receptors due to mucosa dryness; altered chemical or ionic environment in
the region of the receptor due to changes in the
components of saliva or mucus or in agonizing or
antagonizing receptor sites; and changes in neurotransmitter function [139].
As part of the natural aging process that
causes pharmacokinetic and pharmacodynamic
changes, people gradually lose their ability to
smell. Older adults are also at an increased risk
of developing drug-induced olfactory changes
and other adverse drug events, because they take
more prescription and nonprescription medications compared to younger adults [140, 141].
Between 1988 and 2010, the proportion of adults
65 and older taking at least ve medications tripled, from 12.8 to 39.0%, primarily due to
increased use of cardiovascular and antidepressant medications [142]. One survey study found
that dysosmia was higher in those taking more
than four medications per day [7].
Because numerous pathologies can lead to
olfactory dysfunction, a causal relationship must
be established between the medication and the
patient’s symptoms before the event is deemed an
adverse drug reaction. The Naranjo Algorithm,
also known as the Adverse Drug Reaction
Probability Scale, can be used to assess whether
there is a causal relationship. The algorithm is a
series of 10 questions with assigned probability
scores that help determine the likelihood of an
adverse drug event [143]. If it is decided that the
person’s smell dysfunction is indeed caused by a
medication, this medication should be discontinued or switched to an equally efcacious and
safer alternative.
31.4 Summary andFuture
Directions
The olfactory system is a fundamental sensory
system responsible for the perception of avor and
fragrance. Olfaction is critical for most mammals
for the maintenance of a good quality of life.
Scientists and physicians have paid increasing
attention to the olfactory system and its function
during the last decade, largely because of (a)
advances in our understanding of the histocompatibility basis for the receptor mechanisms, (b) evidence that ORNs undergo neurogenesis and both
programmed and induced cell death, (c) important
technical and practical developments in psychophysical testing, and (d) the accessibility of these
cells relatively noninvasively from living subjects
[144–148]. These developments have led to stan-
dardized olfactory testing to assess detection sensitivity (threshold) and ability to identify odors.
These tests can be easy to perform in the clinic and
may be useful in improving diagnosis [149].
Although diagnosis of smell disorders caused
by aging and neurodegenerative diseases has
improved considerably over the last two decades,
treatment of these disorders is still limited to conditions with discernible and reversible causes.
Sensory complaints are often overlooked by the
medical community. Understanding the biological bases for olfactory system disorders can help
us develop new approaches to improve the quality of avor experience for those with impaired
ability. In addition, studies of olfaction and ORN
function may lend new insights into the etiology
of neurodegenerative disease. Future research is
needed for a better understanding of chemosen-
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sory mechanisms, establishing improved diagnostic procedures, and disseminating knowledge
about chemosensory disorders among practitioners and the public [71, 72].
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