Olfactory dysfunction in parkinson disease

REVIEWS

Olfactory dysfunction in Parkinson disease

Richard L. Doty

Abstract | Olfactory dysfunction is among the earliest nonmotor features of Parkinson disease (PD). Such
dysfunction is present in approximately 90% of early-stage PD cases and can precede the onset of motor
symptoms by years. The mechanisms responsible for olfactory dysfunction are currently unknown. As
equivalent deficits are observed in Alzheimer disease, Down syndrome, and the Parkinson–dementia complex
of Guam, a common pathological substrate may be involved. Given that olfactory loss occurs to a lesser
extent or is absent in disorders such as multiple system atrophy, corticobasal degeneration, and progressive
supranuclear palsy, olfactory testing can be useful in differential diagnosis. The olfactory dysfunction in PD
and a number of related diseases with smell loss correlates with decreased numbers of neurons in structures
such as the locus coeruleus, the raphe nuclei, and the nucleus basalis of Meynart. These neuroanatomical
findings, together with evidence for involvement of the autonomic nervous system in numerous PD‑related
symptoms, suggest that deficits in cholinergic, noradrenergic and serotonergic function may contribute to
the olfactory loss. This Review discusses the current understanding of olfactory dysfunction in PD, including
factors that may be related to its cause.

Doty, R. L. Nat. Rev. Neurol. 8, 329–339 (2012); published online 15 May 2012; doi:10.1038/nrneurol.2012.80

Introduction comparisons with other neurological disorders that Smell and Taste Center,
The olfactory system largely determines the flavour feature smell loss, and a summary of the key neuro- University of
and palatability of foods and beverages, and pro- transmitter systems involved. Implications for clinical Pennsylvania School of
vides warning of spoiled foods, dangerous fumes, and practice, such as the potential to use smell testing for Medicine, Hospital of
unhealthy environm­ ents. Of 750 consecutive patients early diagnosis of PD, are also considered. the University of
presenting to the University of Pennsylvania Smell and Pennsylvania, 3400
Taste Center with mainly olfactory dysfunction, 68% The clinical phenotype Spruce Street,
reported altered quality of life, 46% reported changes Since the early 1980s, nearly 100 peer-reviewed psycho­ Philadelphia, PA
in appetite or body weight, and 56% reported adverse physical studies have compared the olfactory function 19104, USA.
influences on daily living or psychological well-being.1 in patients with sporadic PD with that of normal con- doty@
In a recent longitudinal study of 1,162 older indivi­duals trols.5 In essentially all cases, statistically significant mail.med.upenn.edu
without dementia, mortality risk was 36% higher in differences have been observed, regardless of whether
those with low scores on a smell test after adjusting for tests of odour detection, identification, discrimination
such variables as sex, age and education.2 or memory have been employed (Box 1).6 Given that
such tests rely on different odorants and odorant con-
An association is now recognized between early-stage centrations, and have differing reliabilities and cognitive
Parkinson disease (PD) and significant smell dysfunc- demands,7,8 such uniformity of findings is remarkable.
tion, with a prevalence of approximately 90% in sporadic This uniformity largely reflects the fact that most nomi-
PD cases.3 Such dysfunction, along with alimentary, nally disparate psychophysical tests are positively corre-
cardiovascular and autonomic nervous system distur- lated with one another and probably measure the same
bances, has led to the concept that PD is a systemic underlying pathological substrate or substrates.9 When
disease. If this multisystem disease is defined in terms differences are observed in findings among such tests,
of its α‑synuclein-related pathology (α‑syn pathology), a caution is warranted in their interpretation, in light of
case can be made that it begins, at least within the brain, test-related differences in reliability, employment of dif-
in the olfactory bulb, the associated anterior olfactory ferent odorants, and variations in non-olfactory opera-
nucleus (AON), and the dorsal motor nuclear complex tional elements of testing.7,8 Importantly, terms used to
of the glossopharyngeal and vagus nerves, and only later describe such tests, such as detection or identification,
involves the nigrostriatal motor complex (Figure 1).4 need not be congruent with what they actually measure,
and do not represent independent chemosensory pro-
This Review discusses the clinical and patho­physio­ cesses. Thus, an odour cannot be identified or discrimi-
logical features of olfactory dysfunction in PD, including nated from another odour if it cannot be detected, and
memory is required for tests of odour identification,
Competing interests detection and discrimination.
The author declares an association with the following
company: Sensonics. See the article online for full details of
the relationship.

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Key points a 40-item picture test that specifically depicts the items
employed in the involved smell test.
■■ Olfactory dysfunction is an early and sensitive marker of the preclinical phase of
Parkinson disease (PD) Not all neurodegenerative diseases exhibit the degree
of smell loss observed in PD, making olfactory testing
■■ Analogous olfactory dysfunction occurs in other—but not all—neurodegenerative useful in differential diagnosis.15 Thus, olfactory dysfunc-
diseases, suggesting the involvement of a common neuropathological substrate tion is less severe or absent in other neurological dis­
orders that can be mistaken for PD, such as progressive
■■ PD is a multisystem disorder in which brain neuropathology seems to begin in the supranuclear palsy (PSP),16,17 1‑methyl‑4-p­ henyl‑1,2,3,6-
olfactory bulb and the dorsal motor nucleus complex of the glossopharyngeal and tetrahydropyridine (MPTP)-induced parkinson-
vagus nerves ism,18 multiple system atrophy (MSA),17,19 corticobasal
degenera­tion (CBD),17 and essential tremor.20,21 Goldstein
■■ Damage to largely nondopaminergic neurotransmitter systems may contribute et al.,19 for example, proposed that clinical laboratory
to, or possibly even cause, the olfactory loss observed in PD and some other testing to differentiate PD from MSA should begin with
neurodegenerative diseases olfactory testing. Largely because of the use of olfactory
testing in differential diagnosis, the Quality Stand­ ards
■■ Many environmental risk factors for PD, including older age, head trauma, and Committee of the American Academy of Neurology
exposure to metal ions, viruses and pesticides, are also risk factors for smell has suggested that smell tests should be considered in
loss that is independent of PD dif­ ferentiating PD from disorders such as PSP and CBD.22

■■ Air pollution-related toxins, including nanoparticles, can enter the brain via Olfactory dysfunction in PD occurs early in the disease
the olfactory epithelium and induce inflammatory responses and PD-like process and is not altered by levodopa or dopamine ago-
neuropathology in the olfactory bulb and other forebrain structures nists.10 Although most studies have found the dysfunc-
tion to be independent of disease stage, disease duration,
With the above caveats in mind, the olfactory dysfunc- and measures of cognitive function,3,10,23–27 some have
tion in PD can be characterized as bilateral and robust.6,10 noted associations between olfactory test scores and
It differentiates PD from controls better than do clinical measures of verbal learning, memory, or executive
motor tests,11 and as well as or better than single-photon function28–30 and two have reported associations with
emission CT (SPECT) imaging of the dopamine trans- disease duration.12,31 In a PD cohort retested after nearly
porter,12 a membrane protein that pumps dopamine 7 years, a higher risk of developing visual hallucinations
from the synapse back into the cytosol. Specificity for and greater cognitive dysfunction, as measured by the
PD, however, is lacking: as shown in Table 1, the average Unified Parkinson’s Disease Rating Scale (UPDRS),32 was
olfactory dysfunction in PD, which is not total loss, is present in patients with the most olfactory dysfunction
essentially equivalent to that of early-stage Alzheimer at baseline.33 In patients with early-stage PD, correlations
disease (AD), Down syndrome,13 non-Down syndrome have also been reported between olfactory test scores and
mental retardation in children, and the Parkinson– dopamine transporter levels, as measured by PET and
dementia complex of Guam,14 as well as that of myasthe- SPECT imaging, in brain regions including the striatum
nia gravis (results not shown; F. E. Leon-Sarmiento et al., and hippocampus.34–36
unpublished work). The olfactory test results presented
in Table 1 are for individuals capable of understanding
the involved odour concepts and test procedure, as indi-
cated by high scores on the Picture Identification Test,

Braak stages 1 and 2 Braak stages 3 and 4 Braak stages 5 and 6
Autonomic and olfactory Sleep and motor Emotional and cognitive
disturbances
disturbances disturbances

Via olfactory
bulb

Premotor Motor Brainstem Lewy body
symptoms symptoms Cortical Lewy body
Via vagus
nerve

Figure 1 | The Braak staging system of Parkinson disease, showing the initiation sites in the olfactory bulb and the medulla
oblongata, through to the later infiltration of Lewy pathology into cortical regions. α‑Synuclein-related pathology is possibly
initiated in the periphery via input from the olfactory epithelium or vagal inputs from the stomach, perhaps involving
xenobiotic factors. The red shading represents the pattern of pathology. Permission obtained from John Wiley and Sons ©
Halliday, G. et al. Mov. Disord. 26, 1015–1021 (2011).

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The olfactory loss in PD is associated with baroreflex Box 1 | Olfactory tests
failure and noradrenergic denervation of the heart and
other organs.37 For example, olfactory test scores correlate Olfactory tests can be divided into psychophysical tests (for example,
with cardiac sympathetic function.19,38 This association, identification, detection, discrimination and memory of odours),
which is lacking in patients with MSA, is independent electrophysiological tests (for example, odour event-related potentials),
of striatal dopaminergic denervation, disease duration, and psychophysiological tests (for example, odorant-related respiratory
and clinical ratings of motor function, and contributes changes).132–134 Psychophysical tests, which are the most practical, require a
to the concept that PD is a systemic disease with major conscious response.135 More than 20 psychophysical olfactory tests, the majority
autonomic nervous system dysfunction. of which employ some form of odour identification, have been used to assess
olfactory function in Parkinson disease (PD). In most identification tests, familiar
Olfactory dysfunction in predicting PD odorants are presented, and the patient chooses the name of the odour from a
To some extent, olfactory dysfunction is predictive of list of options.136,137 In addition to determination of the absolute level of olfactory
future development of clinical PD, although identifi- function, sex-related and age-related normative data can allow the determination
cation of individuals with premotor PD in the general of a patient’s percentile rank relative to peers.136 In PD‑related studies, odorants
population is limited by low specificity. In the longitu- have been presented from squeeze bottles,23 glass bottles,138 ‘scratch and
dinal Honolulu–Asia Aging Study,39 2,276 asymptom­ atic sniff’ microencapsulated labels,135 felt-tipped-pen-like devices,139 and pieces of
elderly men of Japanese ancestry (mean age 79.7 years) paper smeared with an odorant.140 Culture-specific tests have been developed,
completed a 12-item odour identification test.40 During as some odours are not universally familiar.40,141,142 Threshold tests—in which
a 4‑year follow-up period, 35 participants were diag­nosed the lowest concentration of an odorant that can be discerned is assessed—are
with clinical PD. After adjusting for confounders, those also popular, in part because the results are easy to interpret and the auditory
with olfactory test scores in the lowest quartile had an analogue is familiar to clinicians.143 However, unless the perithreshold region
odds ratio for developing clinical PD of 5.2 compared is repeatedly sampled, reliability is low.7 Odour discrimination tests require the
with those in the two highest quartiles. This relationship patient to pick out the ‘odd’ stimulus from a set of foils.139,144 Odour memory
was not evident beyond the 4‑year period, consistent with tests seek to establish the ability to recognize previously experienced odours
the concept that, in most cases, the preclinical nonmotor over time, but some of these tests can be confounded by semantic issues.138,144
period of PD is probably less than a decade.41–43 Some investigators combine data from threshold tests with those from other
tests into a master score.139 Although this approach increases test reliability,
Most studies attempting to predict PD from olfactory it is questionable from a theoretical perspective if one accepts the premise
test scores have tested asymptomatic first-degree rela- that different attributes are being measured. For example, two people with the
tives of patients with PD, under the assumption that they same test score could have quite different threshold and identification values,
are more likely to develop PD than are non-relatives.44–47 conceivably reflecting different underlying pathologies.
In a pioneering study, Ponsen et al. administered olfac-
tory tests to 361 asymptomatic first-degree relatives of 15th percentile, were more likely than those with higher
patients with PD and performed SPECT imaging of the test scores to report symptoms commonly associated
striatal dopamine transporter in those with olfactory test with PD or with PD risk factors, including rapid eye
scores in the top and bottom deciles.46 After 2 years, four movement sleep behaviour disorder. Other symptoms
of the 40 individuals with initial scores in the bottom that were more commonly reported among hyposmic
decile—all of whom exhibited a reduction in nigro­striatal participants included anxiety, depression, constipation,
dopamine transporter activity at ba­ seline—had devel- and subtle changes in motor function. Whether these
oped clinical PD, whereas none of the 38 individ­ uals individuals have dopamine transporter deficits or will be
with test scores in the top decile did so. In the remain- more prone to develop such deficits or PD in the future
ing hyposmic relatives without PD, the average rate of has yet to be determined in this ongoing study.
decline in dopamine transporter binding was signifi-
cantly higher than that in the normosmic relatives. No Olfaction in genetic forms of PD
individuals with olfactory test scores in the top decile Twin studies suggest that sporadic PD has low herit-
exhibited dopamine transporter deficits or progressed ability,48 but a positive family history of PD among first-
to PD. The researchers concluded that asymptomatic degree relatives is observed in 10–15% of sporadic PD
individ­ uals who have both a first-degree relative with cases in the USA.49 Monogenic forms have also been
PD and an olfactory deficit have at least a 10% chance of identified, the most common being caused by a muta-
developing clinically defined PD. tion in the leucine-rich repeat protein kinase 2 (LRRK2)
gene that results in a Gly2019Ser substitution. This muta-
The assumption that relatives of patients with sporadic tion is associated with approximately 5% of familial and
PD are at higher risk of exhibiting olfactory dysfunction 0.5–2.0% of sporadic PD cases in most populations,
than are non-relatives has recently been called into ques- and with 30–40% of familial or sporadic PD cases in
tion. Siderowf et al. tested the olfactory function of 2,228 North African Arabs and Ashkenazi Jews.50
asymptomatic individuals with one or more first-degree
relatives with PD, and 2,771 asymptomatic individuals Some, but not all, monogenic forms of PD that have
with no first-degree relatives with PD.47 All participants been evaluated are accompanied by olfactory dysfunc-
were over the age of 50 years. The 40-item odour iden- tion similar to that observed in sporadic PD (Table 2).
tification test scores of these two groups did not differ In the cohorts that have been studied, a number of carri-
significantly, although hyposmic individuals from both ers of PD‑related mutations, such as those with LRRK2
groups, defined as those with test scores at or below the mutations who have not yet manifested motor symp-
toms, have normal smell function.51–53 Olfactory loss
in patients with these mutations might be age-related,

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Table 1 | Olfactory test scores in five neurological disorders

Parameter Alzheimer Down Non-Down-syndrome Parkinson Parkinson–dementia
disease syndrome retardation disease complex of Guam

Number of individuals studied 24 16 16 24 24

Mean age in years (SD) 68.7 (8.5) 14.2 (4.5)* 14.3 (4.5) 61.0 (7.7) 60.5 (7.5)

Mean UPSIT score out of 40 (SD) 18.4 (7.1) 19.3 (4.7) 20.8 (8.5) 20.2 (7.1) 20.5 (7.3)

% change in UPSIT score from –46.1 –46.4 –42.4 –44.6 –43.7
matched controls

Mean PIT score out of 40 (SD)‡ 38.3 (1.8) 35.0 (3.1) 36.9 (2.6) 39.5 (0.9) 36.2 (3.4)

*Classic Alzheimer disease-like pathology is not present at this age, and the performance of these patients on the UPSIT test was at the same level as in
children of equivalent IQ with non-Down-syndrome retardation. ‡All individuals achieved high PIT scores, demonstrating preserved ability to perform the
non-olfactory demands of the task and to recognize pictures of the odorants. Abbreviations: UPSIT, University of Pennsylvania Smell Identification Test;
PIT, Picture Identification Test.

and penetrance may occur a few years before the motor concepts of the olfactory vector hypothesis65 and the pro-
dysfunction,39,41,54 conceivably analogous to the olfactory gression of pathology proposed by Braak et al.57 Recent
loss in carriers of the Huntington disease gene.55 Interest­ studies suggest that α‑syn aggregates may be transferred
ingly, the association between olfactory test scores and from cell to cell, providing one means by which the
abnormal cardiac sympathetic function is seen less fre- spread of α‑syn pathology might occur.66
quently in carriers of PD‑associated LRRK2 mutations
than in non-carriers.56 Tau-related pathology
The pathological hallmark of PD, as discussed above, is
Olfactory system pathology the α‑syn-positive Lewy body, but tau-related pathology
α-Synuclein-related pathology in the form of neurofibrillary tangles is also common
The classic signs of PD are most closely associated with in PD.67 Tau is a member of the microtubule-associated
α-syn pathology in the substantia nigra, such as Lewy protein (MAP) family, which regulates and stabilizes
bodies and Lewy neurites. As noted in Figure 1, prior to microtubule assembly. Colocalization of tau-related
these changes such pathology is found within the olfac- and α‑syn pathology is higher than expected by chance,
tory bulbs, the closely associated AON, and a number of leading to the concept that these proteins are func-
secondary olfactory structures (Figure 2).4,57–59 However, tionally related in PD.68 Notably, tau-related pathol-
α‑syn pathology in the olfactory mucosa does not occur ogy occurs in the bulbar component of the AON in
at a level higher than in healthy age-matched controls.60 disorders that are accompanied by marked olfactory
loss—that is, AD, PD, and dementia with Lewy bodies
α�-S��y�n��p�a�t�h�o��lo��g�y��in��t�h�e��o�l�f�a�c�t�o�r�y��b�u��lb��s�d�i�f�f�e�r�e�n�t�i�- —but does not occur in this area in disorders that are
ates neuropathologically confirmed PD from non-PD associated with considerably less or no olfactory loss
elderly controls with a high degree of sensitivity (95%) —that is, PSP and CBD.69,70 In AD, tau-related pathol-
and specificity (91%).61 This pathology is present within ogy appears before amyloid‑β deposition and is found
the main projection neurons of the olfactory bulb—that throughout the olfactory bulb, with the highest level in
is, the mitral and tufted cells—as well as in the axon- the AON.71 Olfactory deficits are seen in transgenic mice
less granule and periglomerular cells (Figure 3).62 α‑Syn that overexpress human tau in their olfactory bulbs.72
pathology seems to first appear in the non-AON areas Such associations suggest that tau may be an important
of the olfactory bulb and then within the AON.62 The contributor to olfactory dysfunction in PD.
cortical nucleus of the amygdala, which receives the pri­
mary olfactory bulb projections, exhibits considerably Neurotransmitter alterations
more α‑syn pathology and neuronal loss than do the PD is associated with altered synaptic transmission at
other major amygdaloid nuclei, which do not receive numerous levels within the olfactory pathways. Damage
such projections.63 The degree of α‑syn pathology in the to both dopaminergic and nondopaminergic neuro-
amygdala is strongly correlated with that in the AON.62 transmitter systems may contribute to the PD‑related
olfactory disorder and could, in theory, precede or even
Other structures receiving mitral and tufted cell catalyse the development of defining neuropathological
projections, such as the piriform cortex and entorhi- characteristics of the disease. Several of the major neuro-
nal cortex (Figure 2), also exhibit substantial numbers transmitter and neuromodulator systems that are altered
of Lewy bodies and Lewy neurites.4,63,64 The temporal in PD and are potentially associated with its olfactory
piriform cortex of patients with PD shows more α‑syn dysfunction are described below.
pathology than does the olfactory tubercle, the frontal
piriform cortex, and the anterior entorhinal cortex, all Acetylcholine
of which exhibit more pathology than the orbitofrontal The nucleus basalis of Meynert—the main source of
cortex.64 Although more research is needed, these find- acetyl­choline in the forebrain—is substantially damaged
ings suggest the possibility of a peripheral to central in PD73,74 and other neurodegenerative disorders that are
spread of α��‑�sy�n��p�a�t�h�o�l�o�g�y��t�h�r�o�u�g�h��t�h�e�m��a�j�o�r�c�o��m�p��o�-
nents of the olfactory system, in accordance with general

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Table 2 | Olfactory function in gene-related forms of parkinsonism

Gene (locus) Protein Inheritance Mutations Clinical features Olfactory Selected references
pattern function
Early-onset disease, Variable and Bostantjopoulou et al. (2001)145
SNCA α-Synuclein Autosomal Ala30Pro, Ala53Thr and dementia and autonomic idiosyncratic; Kruger et al. (1998)146
(4q21–q23) dominant Glu46Lys; duplications dysfunction; rare and not limited data
and triplications yet observed in sporadic Alcalay et al. (2011)147
PD cases Normal Khan et al. (2004)148
PARK2 Parkin Autosomal Wide variety of
(6q25.2–q27) recessive mutations, exonic Juvenile and early-onset Normal or only Eggers et al. (2010)149
PTEN-induced deletions, duplications disease; slow mild loss Ferraris et al. (2009)150
PINK1 putative kinase Autosomal and triplications progression and good
(1p35–p36) protein 1 recessive levodopa response Dysfunction Ferreira et al. (2007)151
Leucine-rich repeat Gly309Asp; similar to Khan et al. (2005)152
LRRK2 kinase 2 Autosomal exonic deletions Early-onset disease, slow classic PD; Markopoulou et al. (1997)153
(12q12) dominant, progression and good possibly slightly Marras et al. (2011)154
incomplete Gly2019Ser levodopa response less loss Silveira-Moriyama et al. (2008)51
penetrance (most common), Silveira-Moriyama et al. (2010)155
Arg1441Cys/Gly/His, Late-onset disease; Dysfunction Goker-Alpan et al. (2008)156
Tyr1699Cys, Ile2020Thr, tremor-dominant PD similar to Saunders-Pullman et al.
Gly2385Arg and others symptoms classic PD (2010)157

GBA Glucocerebrosidase Autosomal Asn370Ser, Leu444Pro, Gaucher disease
(1q21–22) recessive Lys198Thr, Arg329Cys, (hepatomegaly,
c.84dupG thrombocytopaenia,
moderate bone disease);
variable age of onset and
levodopa response

Abbreviation: PD, Parkinson disease.

accompanied by olfactory dysfunction.73 This nucleus that dopamine deficiencies in these regions could be a
is affected to a considerably lesser extent in PSP and determinant of the olfactory loss in PD.16
MSA, diseases in which olfactory function remains
largely intact.17 A recent PET study of 58 patients with Most forebrain dopamine is found in periglo-
PD found relatively strong correlations (r values ranging merular cells of the olfactory bulb. Unlike cells in the
from 0.55–0.63) between scores on a 40-item smell iden- mesoc­ ortical and mesolimbic dopaminergic systems,
tification test and activity of acetycholinesterase, the how­ever, periglomerular cells do not degenerate in PD.
enzyme that breaks down acetylcholine, in the hippo­ In fact, they increase in number, particularly in women.79
campus, amygdala and neocortex.28 Such an association Moreo­ ver, expression of tyrosine hydroxylase, the rate-­
suggests a close relationship between olfactory function limiting enzyme in dopamine synthesis, also increases
and central cholinergic processes in PD. in the olfactory bulb in patients with PD80 and in PD
animal models.81–83
We have recently found that myasthenia gravis—an
autoimmune disease that is classically thought only to In the past decade, significant correlations have been
affect acetylcholine receptors at the muscle motor end found between olfactory test scores and dopamine trans-
plate—is associated with smell loss analogous to that porter activity in the nigrostriatal region and hippo­
of PD (F. E. Leon-Sarmiento et al., unpublished work). campi of patients with PD,12,34,35,84 as well as in elderly
This remarkable discovery supports not only the notion non-PD cohorts.85 Whether such correlations reflect
that myasthenia gravis influences the CNS, but also the causal associ­ations remains to be determined, as both
idea that acetylcholine receptors could play a key part in effects could reflect influences of another process, such as
olfactory dysfunction in a number of diseases, including decreased cholinergic modulation of the neural activity
PD. Importantly, these findings support the theory that of these structures.
the immune system may be involved in the pathogenesis
of a number of neurological disorders.75 Noradrenaline
PD is associated with severe damage to the locus coeruleus
Dopamine —the brain area that sends noradrenergic projections
A defining feature of PD is the degeneration of dopa- to the olfactory bulb and a number of olfaction-related
minergic neurons in the substantia nigra pars compacta forebrain structures. Remarkably, the loss of locus coer-
and in the melanin-containing cells of the ventral teg- uleus noradrenergic neurons is greater than the loss of
mentum.76 The olfactory tubercle and other mesolimbic dopaminergic neurons in the substantia nigra.86 In a
regions receive dopaminergic input from the ventral study of brain tissue from 28 patients with PD, 68% of
tegmentum.77 Interestingly, these regions are relatively cases had α‑syn pathology in the locus coeruleus.87 The
spared in PSP,78 a disorder associated with considerably frequency of such pathology in the locus coeruleus was
less olfactory dysfunction than that in PD, suggesting higher than that observed in the AON (40% of cases),
the olfactory bulb (47% of cases), and the olfactory tracts

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Secondary olfactory structures Olfactory epithelium
Anterior olfactory nucleus Olfactory bulb

Piriform and
periamygdaloid cortices

Neocortex Orbitofrontal and
dorsolateral cortices
Olfactory Entorhinal Amygdala Thalamus
tubercle cortex (corticomedial nuclear group) (mediodorsal nucleus) Insular cortex

Hippocampus

Hypothalamus (supraoptic nucleus)

Pituitary Brainstem region

Circulation Autonomic functions

Figure 2 | The major afferent projections and structures of the olfactory system. Although most of the brain regions that
receive afferent projections from the olfactory bulb are classically considered the primary olfactory cortex, the olfactory
bulb itself can be considered a cortical structure, making this terminology ambiguous.158 For this and other reasons, these
regions are labelled secondary olfactory structures in the figure.

(58% of cases). Co-involvement of the locus coeruleus cortex, entorhinal cortex, frontal cortex, hippocampus
and primary olfactory structures was noted: 73% of the and thalamus.96,97 Lewy bodies are typically found in the
15 cases with α‑syn pathology in the olfactory bulb and raphe nuclei (the origin of 5‑HT projections98), often in
tracts also had α‑syn pathology in the locus coeruleus. conjunction with α‑syn pathology in the locus coeruleus.
For example, in the aforementioned study examining the
Patients who lack dopamine β‑hydroxylase—the locus coeruleus in PD, 83% of the 17 cases with α‑syn
enzyme that converts dopamine into no­radrenaline pathology in this brain region also exhibited such pathol-
—do not synthesize noradrenaline, yet they have rela- ogy in one or more of the serotonergic raphe nuclei.87
tively normal olfactory function. Moreover, depletion of Like noradrenaline, 5‑HT can influence the activity of
olfactory bulb noradrenaline in rats by use of 6‑hydroxy- other neurotransmitters, including dopamine, glutamate
dopamine has no effect on their odour detec­tion per- and �γ�‑�a�m�i�n�o��b�u�t�y�r�ic��a�c�id��. �D�e�p��e�n�d�i�n�g��o�n�t�h�e��5�‑�H��T��re�c�e�p��-
formance.88 These findings suggest that nor­adrenaline tor subtype involved, 5‑HT can either facilitate or inhibit
deficiency per se is unlikely to be the cause of the smell dopamine release from nerve terminals.99
loss observed in PD.89 Noradrenaline does, however,
regulate transcription of inflammatory genes in both The available data, although limited, suggest that PD
astrocytes and microglia,90 and contributes to regula- is associated with loss of 5‑HT-synthesizing neurons
tion of the permeability of the blood–brain barrier.91 from the dorsal raphe nuclei. Such loss is also evident
Nigrostriatal susceptibility to damage from MPTP is in disorders associated with equivalent smell loss to that
increased by lesions to the locus coeruleus in both pri- observed in PD, such as AD, but not in disorders with less
mates and rodents,92,93 and in mice is exacerbated by the olfactory loss, such as PSP and MSA.100 In rats, deafferen­
α2-adrenoceptor antagonist yohimbine and mitigated by tation of 5‑HT fibres ascending into the olfactory bulb
the α2-adrenoceptor agonist clonidine.94 Together, these reportedly produces anosmia.101 Although noradrener­
findings suggest a protective role for noradrenergic input gic fibres are largely spared in these rats, intrabulbar
into the striatum. dopaminergic neurons are reduced in number and the
bulbs are markedly shrunken, with fewer olfactory recep-
Serotonin tor cells, and atrophy of the granule layer as well as the
Serotonin (5‑hydroxytryptamine or 5-HT) is intimately external and internal plexiform layers.102
associated with brain circuits related to smell function.
For example, activation of 5‑HT fibres originating in Inflammation-related pathology
the raphe nuclei can alter the output of activity from Evidence suggests that the olfactory bulb might be
mitral cells, the main projection neurons of the olfactory uniquely vulnerable to pathology associated with
bulb.95 In PD, 5‑HT is markedly depleted in the olfac- inflamm­ ation, most notably that initiated by micro-
tory bulb, as well as in the caudate nucleus, cingulate glia. Under resting conditions, microglia are kept in a

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quiescent state by the coordinated action of neurons Centrifugal Anterior olfactory Olfactory
and astrocytes, including release of neuromodulators axons nucleus tract
such as acetyl­choline and noradrenaline.103 However, G
when such restraints are lifted or when the microglia GG Lateral olfactory
encounter xenobiotics or neural injury, these cells are tract to primary
rapidly activated, changing their morphology, becoming olfactory cortices
phagocytic, and releasing proinflammatory and immune Granule cell layer
regulatory cytokines such as IL‑1 and tumour necrosis
factor.104 If left unchecked, sustained activation of such Internal plexiform layer
inflammation-related factors can result in substantial
neural damage. Damage to cultured dopaminergic cells MM Mitral cell layer
induced by diesel exhaust particles or by MPTP requires
the presence of microglia in the culture, highlighting the T External plexiform layer
importance of microglia in this pathological process.105,106
Glomerular layer
A recent study107 demonstrated that the introduc-
tion of a single small dose of lipopolysaccharide from Olfactory nerve layer
Escherichia coli into the mouse nose resulted in a wide-
spread wave of Toll-like receptor 2 (TLR2) activation, Cribriform plate
starting in the olfactory bulb and progressing throughout
the brain. TLR2 is a receptor that mediates the produc- Olfactory receptor
tion of cytokines involved in immune reactions. The neurons in
olfactory bulb microglia were also uniquely activated by
ischaemic brain injury at a site distant from the olfac- olfactory epithelium
tory bulb hours before microglial activation occurred in
tissues near the injury, and remained for months after Figure 3 | Schematic diagram showing major layers of the olfactory bulb and
the injury. The researchers hypothesized that olfactory interactions between different types of bulbar cells. The small internal plexiform
bulb microglia are functionally unique and crucial for layer, located between the granule cell and mitral cell layers, is not shown. Cells near
immunological responses in the brain, reflecting their glomeruli, some of which communicate with glomeruli as shown, are termed
anatomically distinct position at the interface between periglomerular cells. Abbreviations: G, granule cell; M, mitral cell; T, tufted cell.
the external environment and the brain. Permission obtained from Elsevier Ltd © Duda, J. E. J. Neurol. Sci. 289, 49–54 (2010).

Role of environmental factors receptor cells and are subsequently transporte­ d to
Despite the aforementioned advances in identify- synapt­ic vesicles.117
ing neurop­ athology and neurotransmitter alterations Air pollution
in the olfactory system of patients with PD, the spe- Xenobiotics found in diesel exhaust and air pollution
cific pathophysiological mechanisms responsible for initiate PD‑like and AD‑like neuropathology in human
the olfactory loss remain enigmatic. Like sporadic PD olfactory bulbs, as reflected by neuroinflammation, oxi-
itself, herita­ bility estimates for measures of olfactory dative stress, DNA damage, and upregulation of neuro-
function, particularly in older age groups, are generally degenerative-disease markers.111,118 Postmortem studies
low.108 It may not be coincidental that most risk factors have identified the accumulation of ultrafine (<100 nm
for PD—including age109 and head trauma,110 and expo- in diameter) particulate matter and inflammatory media-
sure to nano­particles,111 viruses,112 ionized metals113 and tors in the olfactory epithelia and bulbs of children and
pesticides114—are also risk factors for smell loss that is young adults from highly polluted areas of Mexico
in­dependent of PD. City.111 A number of these individuals exhibit abnor­
mal immunoreactivity to α‑syn and amyloid‑β in cells
Olfactory receptor cells are susceptible to damage from of the olfactory bulb and in other brain structures within
xenobiotic agents, given that they are directly exposed the brains­ tem and forebrain.119,120 Importantly, subtle
to the environment. They are also vulnerable to xeno­ but statistically significant decrements in smell function
biotic invasion, having long cilia that collectively provide have been found in young residents from these polluted
a ~23 cm2 exposed surface area, and axons that project regions of Mexico City relative to those in less-polluted
directly into the brain from the nasal cavity without an
intervening synapse.115 The olfactory neuroepithelium
is widely distributed throughout the nasal cavity, lining
the dorsal septum, cribriform plate, and sectors of the
middle and superior turbinates.116 In accordance with the
olfactory vector hypothesis,65 numerous xenobiotics have
been shown to be capable of bypassing the blood–brain
barrier and penetrating the brain via this specialized epi-
thelium.111 Some agents move along extran­ eural spaces
in the nerve bundles of the olfactory fila, whereas others
undergo receptor-mediated endocytosis by olfactory

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cities111—decrements similar to those of workers exposed most common cause of chronic, often permanent, smell
to airborne toxic pollutants that were present following loss in the general population.1 Like manganese and
the collapse of the World Trade Center in New York.121 some other metals, viruses can enter the brain via the
olfactory mucosa and, in some cases, move through
Manganese the olfactory pathways to multiple brain regions.65 For
Airborne exposure to manganese in occupational set- example, in the rat, herpes simplex virus type I migrates
tings has been associated with olfactory loss.122 Transp­ ort from the olfactory bulb into cholinergic neurons in
of this metal through the olfactory mucosa depends on the horizontal limb of the diagonal band, serotonergic
the divalent metal transporter‑1 (DMT1) and is facili- neurons in the raphe nuclei, and noradrenergic neurons
tated by iron deficiency.123 Manganese exposure has been in the locus coeruleus.131
associated with a threefold to 10-fold increased risk of
developing classic PD,124 although most parkinsonism Conclusions
attributed to such exposure differs from PD on clinical A key element of the preclinical stage of PD is impaired
and pathological grounds, producing a syndrome termed olfactory function, with an estimated 90% of sporadic
manganism.125 Some researchers have suggested that cases, as well as some monogenic forms, exhibiting
acute exposure to high levels of manganese damages the such loss. The impairment, which is rarely complete
globus pallidus and induces manganism, whereas chronic smell loss, is robust, bilateral, independent of dopa-
exposure to low levels of manganese results in cumulative mine therapy and, in the case of sporadic PD, correlated
damage to the substantia nigra, and exp­ ression of PD.126 with abnormal cardiac sympathetic function. In some
cases the loss is present years before the onset of the
MPTP motor symptoms. The basis for the dysfunction is pres-
The most-studied xenobiotic directly linked to parkin- ently enigmatic, although decrements in several neuro­
sonism is MPTP. This compound has a chemical struc- transmitter systems may be involved. Interestingly, most
ture similar to that of the herbicide paraquat, which risk factors for PD are also risk factors for olfactory dys-
has also been associated with PD.127 Rodent studies function that is independent of PD, including age, head
have found that intranasal exposure to MPTP is gen- trauma, and exposure to metal ions, viruses and pesti-
erally more effective than intraperitoneal exposure cides. As the olfactory dysfunction of PD is essentially
in producing PD‑like behavioural and physiological identical to that of neurological disorders such as AD,
motor symptoms.128 Such exposure induces olfactory Down syndrome, the Parkinson–dementia complex of
loss and a pattern of sequential cognitive and motor Guam, and myasthenia gravis, a common underlying
changes similar to that seen in PD, albeit on a shorter neuropathological substrate is likely. The fact that olfac-
time scale.129 In one study, a single intranasal infusion of tory dysfunction is considerably less common and less
MPTP in rodents resulted in the development of olfac- severe in PSP, MSA and CBD has made olfactory testing
tory dysfunction and PD‑like behavioural deficits.129 useful in differential diagnosis.
These deficits were associated with decreased dopa­
minergic and noradrenergic signalling in various brain Review criteria
areas, and reflected glutamatergic excitotoxicity, mito-
chondrial dysfunction, oxidative stress, and activation Articles included in this Review were selected from
of apoptotic cell death mechanisms. multiple sources, including PubMed and ISI Web of
Science. Search terms included crosses between
Viruses “smell” or “olfaction” and “Parkinson’s disease”,
Viruses are another type of xenobiotic to have been his- “neurotransmitters and Parkinson’s disease”, and related
torically associated with PD. Indeed, before the discovery terms. All available years were accessed, and appropriate
of MPTP and monogenic forms of PD, viruses were con- papers that were available in English were obtained.
sidered to be the primary or even sole cause of PD.130 It is Some papers were translated from Japanese, although
noteworthy that viral upper respiratory infections are the none was included in the final review. Reference lists of
prior reviews and publications were also searched.

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