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Contents
1. Introduction 542
2. Mechanisms of Olfaction and Gustation 542
3. Pathology 544
4. Testing Anosmia and Ageusia 545
5. Prevalence and Course of Anosmia and Ageusia in PD 547
6. Associated Features 548
7. Olfactory and Gustatory Dysfunction in Other Conditions 549
8. Treatment 550
9. Conclusion 551
References 551
Abstract
Anosmia, the loss of sense of smell, is a common nonmotor feature of Parkinson’s dis-
ease (PD). Ageusia, the loss of sense of taste, is additionally an underappreciated non-
motor feature of PD. The olfactory tract is involved early in PD as indicated by frequent
occurrence of hyposmia or anosmia years or decades before motor symptoms and by
autopsy studies showing early synuclein pathology in the olfactory tract and anterior
olfactory nucleus even in the early stages of PD. Testing for olfaction consists of eval-
uation of olfactory thresholds, smell identification and discrimination, and olfactory
memory. Testing for gustation involves evaluating thresholds and discrimination of five
basic tastes (salty, sweet, bitter, sour, and umami). The presence of a specific pattern of
loss in both olfaction and gustation in PD has been proposed, but this has not yet been
confirmed. Within PD, olfactory loss is strongly tied with cognitive status though links to
other features of PD or a particular PD phenotype is debated. Hyposmia is more often
present and typically more severe in PD patients than other parkinsonian syndromes,
making it a potentially useful biomarker for the disease.
1. INTRODUCTION
Parkinson’s disease (PD) is generally considered primarily a motor dis-
order, but there may be nonmotor and sensory features associated with this
common neurodegenerative that may precede and be more disabling than
the motor features (Barone et al., 2009; Patel, Jankovic, & Hallett, 2014).
Anosmia, the loss of the sense of smell, is a nonmotor feature of PD known
to often predate the onset of motor symptoms by at least 4 years (Ross et al.,
2008). Idiopathic olfactory dysfunction (hyposmia) may be associated with a
10% increased risk of developing PD (Ponsen et al., 2004). Another study by
the same team of investigators showed that after 5 years of prospective
follow-up 5/40 (12.5%) of hyposmic first degree relatives of patients with
PD fulfilled clinical diagnostic criteria for PD; none of the other 349 relatives
available for follow-up developed PD (Ponsen, Stoffers, Wolters, Booij, &
Berendse, 2010). Furthermore, all hyposmic individuals developing PD had
an abnormal baseline beta-CIT SPECT scan. Despite the identification of
olfactory dysfunction in PD more than 40 years ago (Ansari & Johnson,
1975), the mechanism behind this dysfunction and its relationship to
etiopathology of PD is still not well understood. Olfactory deficit is relevant
not only also to PD but to aging in general as mortality for anosmic older
adults has been found to be four times that of normosmic individuals and
olfactory function is one of the strongest predictors of 5-year mortality
(Pinto, Wroblewski, Kern, Schumm, & McClintock, 2014).
Gustation, the body’s other major chemosensory system, is closely linked
with olfaction, and indeed ageusia, the loss of taste function, has also been
described in PD (Cecchini et al., 2014; Doty et al., 2015; Kim et al., 2011;
Shah et al., 2009). In this review, to avoid confusion the terms hyposmia
(reduced sense of smell) and hypogeusia (reduced sense of taste) will be omit-
ted in favor of the terms anosmia and ageusia, though in a strict sense these
latter terms refer to a complete lack of respective sensations.
Fig. 1 Olfactory sensory neurons responding to specific odorants complex with mitral
cells which then send afferent fibers via the olfactory tract to the primary olfactory cor-
tex, amygdala, entorhinal cortex, and other cortical structures. Taste receptor cells
respond to tastants via afferent fibers of cranial nerves VII, IX, and X which project to
the solitary nucleus. From here fibers project to the ventral posteromedial nucleus of
the thalamus and more diffusely.
544 Arjun Tarakad and Joseph Jankovic
nerves VII, IX, and X. From here, neurons project to the ventral post-
eromedial nucleus of the thalamus to the primary gustatory cortex (com-
prised of portions of the insular cortex and frontal operculum) (Cecchini,
Fasano, Boschi, Osculati, & Tinazzi, 2015; Maheswaran et al., 2014). It is
important to note that other somatosensory sensations including hot or cool
sensations conveyed by various types of foods and spices, and appreciated via
stimulation of cranial nerves V, IX, and X, can have a significant impact on
gustation, as can olfaction.
3. PATHOLOGY
Anosmia may predate motor symptoms of PD by years or even
decades; hence, it may be the earliest sign of central nervous pathology in
this disease (Barone et al., 2009; Gallagher, Lees, & Schrag, 2010). Gross
examination of the olfactory epithelium and olfactory bulb in patients with
PD is essentially normal (Witt et al., 2009). In one study of PD patients who
had difficulty in discriminating between odors of mothballs, chocolate,
Turkish coffee, and soap the olfactory bulb volume, measured by magnetic
resonance imaging (MRI), showed no difference between the patient and
the control groups (Altinayar et al., 2014).
There is, however, growing evidence that anosmia is associated with
abnormalities in central regions involved in odor perception. MRI diffusion
weighted imaging showed significant increases of diffusivity in the region of
both olfactory tracts in patients with PD compared to controls (Scherfler
et al., 2006). Braak et al. demonstrated α-synuclein deposition in the olfac-
tory tract and anterior olfactory nucleus on pathological examination of
patients even in the earliest stages of PD (Braak, Del Tredici, et al.,
2003). Pathological examination of the brains of PD patients has demon-
strated dysfunction across multiple olfactory receptor genes, when compared
to age-matched controls (Garcia-Esparcia et al., 2013). The initial work of
Braak et al. led to the hypothesis that the development of PD may be initially
triggered by exposure to an external pathogen. This has primarily been con-
sidered through theoretical spread from the gut via the vagus nerve to the
brain stem (Braak, R€ ub, Gai, & Del Tredici, 2003). Because of the paucity
of direct connectivity of the olfactory bulbs to portions of the brain affected
by PD causing more traditional motor symptoms, the significance of olfac-
tory dysfunction and α-synuclein deposition within these structures has been
less rigorously pursued. Nevertheless, dopaminergic innervation of the
olfactory system has been demonstrated in humans (H€ oglinger et al.,
2015), and additionally the spread of human α-synuclein monomers and
Anosmia and Ageusia in Parkinson’s Disease 545
oligomers has been demonstrated in mice from uptake in the olfactory bulb
cells to distally connected brain regions (Rey, Petit, Bousset, Melki, &
Brundin, 2013). It has also been suggested that the effects of PD pathology
on olfaction may be manifested through cholinergic, noradrenergic, and
serotonergic pathways, in line with the view of PD as a manifestation of neu-
rotransmitter dysfunction that extends beyond the dopaminergic system
(Doty, 2012, 2017). In particular, the cholinergic system has been suggested
to play a prominent role in olfactory dysfunction in PD and other neurode-
generative diseases (Doty, 2017; Versace et al., 2017).
The pathology behind ageusia is less well described, and despite its rel-
ative proximity to the dorsal motor nucleus which is affected early in PD, the
solitary tract is largely free of Lewy body pathology even in late-stage PD
(Braak, Del Tredici, et al., 2003). Genetic studies have demonstrated dys-
regulation of taste receptor genes (as with olfactory receptor genes) in PD
patients as compared to controls (Garcia-Esparcia et al., 2013). Interestingly,
all taste receptor genes found to be affected were those involved in the per-
ception of bitterness. Taste perception in PD is more complicated than a
comprehensive reduction in gustatory sensitivity, but rather shows some
selectivity in altered function. In one recent study of 29 early PD patients
and matched controls, whole mouth taste test (WMT) identification was
reduced in PD patients, but relative intensity ratings were increased more
so in the anterior tongue than in the posterior tongue. This was hypothe-
sized to be the result of CN IX (posterior tongue gustatory sensation) dam-
age impairing perception and also releasing central inhibition of CN VII
(anterior tongue gustatory sensation) (Doty et al., 2015). Aside from direct
effects on taste receptors, medications and alterations in saliva production
can influence taste sensation (Maheswaran et al., 2014).
relative to sucrose (sweet) and citric acid (sour) (Doty et al., 2015). In
another study which examined detection and relative pleasantness of sucrose
solutions between 20 patients with PD and age-matched controls, no differ-
ence was found in chemosensitivity between groups (Sienkiewicz-Jarosz
et al., 2013), reinforcing the notion that ageusia may show some selectivity.
This is supported by the observation of taste receptor gene dysregulation
particularly in receptors responsible for the perception of bitterness
(Garcia-Esparcia et al., 2013).
6. ASSOCIATED FEATURES
Anosmia affects men more than women with PD when matched on
severity of PD by motor Unified Parkinson’s Disease Rating Scale
(UPDRS) scores, but this difference was not apparent in healthy age-
matched controls (Liu et al., 2015). Olfactory dysfunction positively corre-
lates with age (Doty, 2009), and as such, while anosmia may be more readily
detectable in older patients with PD, its diagnostic utility may be greater
when present in younger patients with PD.
Not only do cigarette smokers have lower incidence of PD (Li, Li, Liu,
Shen, & Tang, 2015), but PD patients who smoke have less decline in olfac-
tory function when compared to those who do not smoke (Sharer, Leon-
Sarmiento, Morley, Weintraub, & Doty, 2015). This is in sharp contrast
to the general population, where smoking is associated with impairment
of olfactory function (Katotomichelakis et al., 2007). While depression is
associated with olfactory impairment, and more severe olfactory impairment
is associated with depression (Kohli, Soler, Nguyen, Muus, & Schlosser,
2016), depression specifically in PD has not been shown to affect perfor-
mance on olfactory testing when compared to PD patients without depres-
sion (Morley et al., 2011; Rossi et al., 2015).
While anosmia on its own is not associated with any particular PD phe-
notype (Fereshtehnejad et al., 2015; Rossi et al., 2016), in the presence of
REM sleep behavior disorder (RBD), anosmia may be associated more with
the postural instability and gait difficulty form of PD (Kang, Lee, Seo,
Kim, & Koh, 2016). However, it should be noted that RBD on its own
tends to be also associated with this phenotype (Fereshtehnejad et al.,
2015; Kang et al., 2016).
Anosmia has been associated with lower scores on cognitive testing and
may be a predictor of emergent PD-related dementia (Baba et al., 2012).
Cognitive impairment, regardless of etiology, may negatively impact olfac-
tory function and vice versa (Ham et al., 2016). Furthermore, the combina-
tion of cognitive impairment and anosmia is typically associated with more
Anosmia and Ageusia in Parkinson’s Disease 549
with PD (Goldstein et al., 2008). Another study found that PD patients per-
formed significantly worse than those with MSA and progressive supra-
nuclear palsy (PSP) in odor identification tests (Krismer et al., 2017).
Interestingly, PD patients have been demonstrated to have smaller olfactory
bulbs and olfactory tracts relative to those with atypical parkinsonism (spe-
cifically MSA, PSP, and corticobasal degeneration) (Sengoku et al., 2015).
Finally and not necessarily directly related to the main topic, it is inter-
esting to note that some scientists have raised the possibility that people with
early PD develop skin changes that produce a particular odor which can be
smelled by trained individuals who can apparently differentiate patients with
PD from healthy controls (Parkinson’s UK—Skin odour could lead to early
diagnosis of Parkinson’s, n.d.). If confirmed, this could potentially serve as an
early biomarker for PD (Table 1).
8. TREATMENT
Unlike most motor and some nonmotor symptoms of PD, anosmia
and ageusia do not respond to levodopa or other symptomatic medications.
Anosmia and Ageusia in Parkinson’s Disease 551
9. CONCLUSION
Anosmia represents a prominent feature of PD, present in a majority of
patients, and may precede the onset of motor symptoms by years or decades.
While ageusia is less well studied in PD, both anosmia and ageusia represent
nonmotor features of PD that may impact quality of life of patients with PD.
These sensory symptoms are subject to ongoing research, and of potential
value for the development of disease-specific biomarkers in the future.
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