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Optimizing odor identification testing as quick and accurate diagnostic tool for Parkinson's disease

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Introduction: The aim of this study was to evaluate odor identification testing as a quick, cheap, and reliable tool to identify PD. Methods: Odor identification with the 16-item Sniffin' Sticks test (SS-16) was assessed in a total of 646 PD patients and 606 controls from three European centers (A, B, and C), as well as 75 patients with atypical parkinsonism or essential tremor and in a prospective cohort of 24 patients with idiopathic rapid eye movement sleep behavior disorder (center A). Reduced odor sets most discriminative for PD were determined in a discovery cohort derived from a random split of PD patients and controls from center A using L1-regularized logistic regression. Diagnostic accuracy was assessed in the rest of the patients/controls as validation cohorts. Results: Olfactory performance was lower in PD patients compared with controls and non-PD patients in all cohorts (each P < 0.001). Both the full SS-16 and a subscore of the top eight discriminating odors (SS-8) were associated with an excellent discrimination of PD from controls (areas under the curve ≥0.90; sensitivities ≥83.3%; specificities ≥82.0%) and from non-PD patients (areas under the curve ≥0.91; sensitivities ≥84.1%; specificities ≥84.0%) in all cohorts. This remained unchanged when patients with >3 years of disease duration were excluded from analysis. All 8 incident PD cases among patients with idiopathic rapid eye movement sleep behavior disorder were predicted with the SS-16 and the SS-8 (sensitivity, 100%; positive predictive value, 61.5%). Conclusions: Odor identification testing provides excellent diagnostic accuracy in the distinction of PD patients from controls and diagnostic mimics. A reduced set of eight odors could be used as a quick tool in the workup of patients presenting with parkinsonism and for PD risk indication. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Optimizing Odor Identification
Testing as Quick and
Accurate Diagnostic Tool for
Parkinson’s Disease
Philipp Mahlknecht, MD, PhD,
1,2
Raimund Pechlaner, MD, PhD,
1
Sanne Boesveldt, PhD,
3,4
Dieter Volc, MD,
5
Bernardette Pinter, MD,
1
Eva Reiter, MD,
1
Christoph M
uller, MD,
1
Florian Krismer, MD,
1
Henk W. Berendse, MD, PhD,
3
Jacobus J. van Hilten, MD, PhD,
6
Albert Wuschitz, MD,
5
Wolfgang Schimetta, PhD,
7
Birgit H
ogl, MD,
1
Atbin Djamshidian, MD, PhD,
1
Michael Nocker, MD,
1
Georg G
obel, PhD,
8
Arno Gasperi, MD,
9
Stefan Kiechl, MD,
1
Johann Willeit, MD,
1
Werner Poewe, MD,
1
and
Klaus Seppi, MD
1
*
1
Department of Neurology, Medical University Innsbruck, Innsbruck,
Austria
2
Sobell Department of Motor Neuroscience and Movement
Disorders, UCL Institute of Neurology, London, United Kingdom
3
Department of Neurology, Neuroscience Campus Amsterdam, VU
University Medical Centre, Amsterdam, The Netherlands
4
Divisions
of Human Nutrition, Wageningen University, Wageningen, The
Netherlands
5
Study Center Confraternitaet-PKJ Vienna, Vienna,
Austria
6
Department of Neurology, Leiden University Medical Centre,
Leiden, The Netherlands
7
Department of Applied Systems Research
and Statistics, Johannes Kepler University Linz, Linz, Austria
8
Department of Medical Statistics, Informatics and Health
Economics, Medical University Innsbruck, Innsbruck, Austria
9
Department of Neurology, Hospital of Bruneck, Bruneck, Italy
ABSTRACT
Introduction: The aim of this study was to evaluate
odor identification testing as a quick, cheap, and reli-
able tool to identify PD.
Methods: Odor identification with the 16-item Sniffin’
Sticks test (SS-16) was assessed in a total of 646 PD
patients and 606 controls from three European centers
(A, B, and C), as well as 75 patients with atypical par-
kinsonism or essential tremor and in a prospective
cohort of 24 patients with idiopathic rapid eye move-
ment sleep behavior disorder (center A). Reduced odor
sets most discriminative for PD were determined in a
discovery cohort derived from a random split of PD
patients and controls from center A using L1-
regularized logistic regression. Diagnostic accuracy
was assessed in the rest of the patients/controls as
validation cohorts.
Results: Olfactory performance was lower in PD
patients compared with controls and non-PD patients
in all cohorts (each P<0.001). Both the full SS-16 and
a subscore of the top eight discriminating odors (SS-8)
were associated with an excellent discrimination of PD
from controls (areas under the curve 0.90; sensitiv-
ities 83.3%; specificities 82.0%) and from non-PD
patients (areas under the curve 0.91; sensitivities
84.1%; specificities 84.0%) in all cohorts. This
remained unchanged when patients with >3 years of
disease duration were excluded from analysis. All 8
incident PD cases among patients with idiopathic rapid
eye movement sleep behavior disorder were predicted
with the SS-16 and the SS-8 (sensitivity, 100%; posi-
tive predictive value, 61.5%).
Conclusions: Odor identification testing provides
excellent diagnostic accuracy in the distinction of PD
patients from controls and diagnostic mimics. A
reduced set of eight odors could be used as a quick
tool in the workup of patients presenting with parkin-
sonism and for PD risk indication. V
C2016 The Authors.
Movement Disorders published by Wiley Periodicals,
Inc. on behalf of International Parkinson and Move-
ment Disorder Society
Key Words: Parkinson’s disease; parkinsonism;
tremor; diagnosis; olfactory dysfunction
Olfactory deficits affect 75% to 90% of patients
with Parkinson’s disease (PD), and olfactory testing
may also represent a sensitive screening test for indi-
viduals at risk of developing PD,
1-4
whereas olfactory
function is normal or only mildly impaired in other
forms of degenerative parkinsonism or essential
------------------------------------------------------------------------------------------------------------------------------
This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
*Correspondence to: Dr. Klaus Seppi, Department of Neurology, Univer-
sity of Innsbruck, A-6020 Innsbruck, Anichstraße 35, Innsbruck, Austria;
E-mail: klaus.seppi@uki.at
Funding agencies: The assessment of the patients enrolled in Inns-
bruck, Austria, took place as part of studies supported by funds of the
Austrian Science Fund (FWF KLI82-B00), the Medical University Inns-
bruck (MFI 6169), and the Oesterreichische Nationalbank (Austrian Fed-
eral Bank, Anniversary Fund, project no.: 14174). The Bruneck Study
was supported by the “Pustertaler Verein zur Praeavention von Herz-und
Hirngefaesserkrankungen,” the Gesundheitsbezirk Bruneck;, the mayor
of Bruneck, and the “Assessorat fuer Gesundheit”, Province of Bolzano,
Italy.
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online ver-
sion of this article.
Received: 8 January 2016; Revised: 10 February 2016; Accepted: 29
February 2016
Published online 00 Month 2016 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.26637
BRIEF REPORT
Movement Disorders, Vol. 00, No. 00, 2016 1
tremor (ET).
2,5
Olfactory testing has recently been
incorporated in the newly established International
Parkinson and Movement Disorder Society criteria for
PD
6
and prodromal PD.
7
To test for olfactory performance in PD, most stud-
ies have focused on odor identification using the dis-
posable University of Pennsylvania Smell Identification
Test (UPSIT) or the reusable Sniffin’ Sticks test battery
assessing olfactory threshold and odor discrimination
in addition to odor identification.
2,8
Both tests are
time-consuming, and olfactory testing is rarely per-
formed in clinical routine. Most of existing shortened
versions of odor identification tests were not specifi-
cally developed for PD patients, nor were any of these
tests properly validated.
9-13
Hence, we sought to assess the diagnostic value of
the 16-item Sniffin’ Sticks identification subtest (SS-16)
as an easy-to-use, inexpensive tool. We also aimed to
shorten and optimize it to identify both established
and early/prodromal PD using a discovery cohort and
different validation cohorts.
Patients and Methods
For the present study, data from a total of 134 PD
patients and 46 patients with atypical parkinsonism (23
multiple system atrophy [MSA], 23 progressive supra-
nuclear palsy [PSP]), who participated in three inde-
pendent prospective, cross-sectional clinical studies at
the Department of Neurology, Innsbruck Medical Uni-
versity (Innsbruck, Austria)
14,15
and from 336 age-
matched healthy controls (HCs) and 29 subjects with
ET from the prospective population-based Bruneck
Study
16,17
were analyzed (center A). Patients were regu-
larly followed over at least 24 months to reassess their
clinical diagnosis, and 4 cases were reclassified as MSA
(n 51) or PSP (n 53) during clinical follow-up. PD
patients and HCs from center A were randomly split
into approximately equal parts. Patients with MSA,
PSP, and ET were subsumed as differential diagnoses
(DDs) in the validation cohort only (Supporting Fig. 1).
Two independent sets of PD patients and HCs were
used as additional validation cohorts; 400 PD patients
and 150 HCs from the Departments of Neurology of
the VU University Medical Centre (Amsterdam, The
Netherlands) and the Leiden University Medical Centre
(Leiden, The Netherlands) (center B);
18
and 112 consec-
utive PD patients and 120 controls recruited by general
neurologists in Vienna, Austria (center C). Last, we
used a previously described prospective cohort of 24
patients with polysomnography-confirmed idiopathic
rapid eye movement sleep behavior disorder (iRBD),
19
consecutively recruited at center A. iRBD patients were
tested for olfactory function at baseline and followed
up for a mean of 6 years in order to detect incident neu-
rodegenerative diseases, in particular, PD. Studies were
approved by the local ethics committees. All partici-
pants gave written informed consent according to the
Declaration of Helsinki.
Olfactory testing was performed with the SS-16 (Bur-
ghart Medizintechnik, Germany) as described elsewhere.
20
In center C, the Sniffn’ Sticks 12-item odor identification
test (SS-12),
21
a commercially available, shorter version of
the SS-16 test, was used. Subscores of reduced sets of odors
were derived for the present analyses.
Group comparisons between PD patients and con-
trols or DDs were performed with appropriate tests
(see table legends). Odor sets predictive of PD were
determined in the discovery cohort by L1-regularized
logistic regression implementing the least absolute
shrinkage and selection operator (the LASSO)
22
using
the glmnet R package. The performance of full and
reduced odor sets in discriminating PD from controls
or DDs was gauged using area under the receiver
operating characteristic curve (AUC) with respective
95% confidence intervals (95% CI). Performance of
full and reduced odor sets is given by conventional
measures of diagnostic accuracy. To adjust for the
bias in prevalence of PD versus DDs in our pooled
cohort from center A, positive predictive values (PPVs)
and negative predictive values (NPVs) were modeled
for two additional scenarios using published data on
the relative prevalence of PD versus DDs (1) as
reported in general neurological services and (2) as
assumed in specialized movement disorder services.
23
Furthermore, we evaluated the accuracy of the SS-16
and its subscores in (1) identifying PD in cohort A
after excluding patients with >3 years of disease dura-
tion and (2) predicting incident PD among the 24 idio-
pathic RBD patients. SPSS (version 22.0; IBM Corp.,
Armonk, NY) and R software (version 3.2.2; R Foun-
dation for Statistical Computing, Vienna, Austria)
were used for statistical analyses. The local signifi-
cance level was set at P<0.05. Full methods can be
found in the Supporting Appendix.
Results
Characteristics of the patients and controls in the
different cohorts are shown in Table 1A and in the
Supporting Information. Figure 1A and Supporting
Table 1 depict differences in identifying individual
odors in the study groups.
An increasing discriminatory power in the distinction
of PD patient versus HC, as demonstrated in AUCs,
was achieved with an increasing number of odor items
used in the discovery cohort (Fig. 1B). This could be
reproduced in the validation sets, reaching the 95%
confidence interval (CI) of AUCs achieved with the
entire Sniffin Sticks tests (SS-16 and SS-12; upper and
lower row in Fig. 1B, respectively) when using only six
sticks and the optimum when using eight (SS-8). We
assessed diagnostic accuracy of the SS-16 and SS-8 in
identifying PD patients (Table 1B). Of note, all 4
MAHLKNECHT ET AL
2Movement Disorders, Vol. 00, No. 00, 2016
TABLE 1. 
A: Characteristics of the groups
Center A
(Innsbruck and Bruneck)
Centre B
(Leiden)
Centre C
(Vienna)
HCs 5336 PD 5134 DDs 575 MSA 523 PSP 523 ET 529 iRBD 524 HCs 5150 PD 5400
Controls 5
120 PD 5112
Age
a
68.8 68.3
P50.99
68.0 68.8 68.8 69.7
P50.99
63.3 68.9
P50.090
67.2 66.2
P50.99
74.5 69.8
P50.012
66.0 65.0 59.2 67.4
P50.022
61.4 69.9 67.4 610.4
P50.54
69.2 68.6
Female (%)
b
53.6
P50.003
37.3 48.0
P50.35
52.2
P50.75
30.4
P50.99
58.6
P50.17
12.5 42.0
P50.38
37.5 58.3
P50.24
50.0
Disease dura-
tion (yr)
a
NA 6.2 64.8 8.0 614.1
P50.99
4.2 63.2
P50.081
3.1 62.0
P50.006
18.7 618.0
P<0.001
0.8 61.3 NA 11.4 66.3 NA 6.8 65.4
H&Y
a
NA 2.4 60.9 3.2 60.7
P<0.001
3.3 60.9
P<0.001
3.0 60.7
P50.002
NA NA NA 2.6 60.8 NA 2.0 60.7
UPDRS-III
a
NA 31.3 615.1 36.9 611.5
P50.002
43.0 69.2
P<0.001
30.9 610.4
P50.99
NA 2.7 62.9
MMSE
a
28.5 61.5
P50.99
28.8 61.3 27.7 62.2
P50.018
27.2 62.4
P50.60
27.0 62.1
P50.003
28.6 61.7
P50.99
27.4 62.6
SS-12 Sum
a
9.8 62.1
P<0.001
5.4 62.5 9.1 61.9
P<0.001
9.1 61.6
P<0.001
8.4 62.1
P<0.001
9.5 61.9
P<0.001
10.3 61.9
p<0.001
6.5 62.7
SS-16 Sum
a
12.7 62.7
P<0.001
6.8 63.1 11.8 62.4
P<0.001
11.7 62.1
P<0.001
10.9 62.6
P<0.001
12.6 63.7
P<0.001
9.9 64.4 12.6 62.3
P<0.001
7.4 63.0
B: Diagnostic accuracy of the SS-16 and the SS-8 in the identification of PD in the various cohorts
Set of
Odors
AUC
(95% CI) Cutoff
Sensitivity
(95% CI)
Specificity
(95% CI)
Specificity
vs. MSA
Specificity
vs. PSP
Specificity vs.
ET
Accuracy
(95% CI)
Discovery:
PD vs. HC
(center A)
SS-16 0.91 (0.87–0.95) 10 85.9% (75.8–92.4) 86.1% (80.1–90.6) 86.1% (81.1–89.9)
SS-8 0.91 (0.87–0.95) 5 88.7% (79.1–94.4) 84.4% (78.2–89.1) 85.7% (80.7–89.5)
Validation:
PD vs. HC
(center A)
SS-16 0.93 (0.90–0.97) 10 92.1% (82.3–97.0) 86.5% (80.3–91.0) 88.5% (83.1–91.7)
SS-8 0.94 (0.91–0.97) 5 93.7% (84.3–98.0) 84.0% (77.6–88.9) 86.7% (81.6–90.6)
Validation:
PD vs. DD
(center A)
SS-16 0.92 (0.87–0.96) 10 92.1% (82.3–97.0) 76.0% (65.1–84.3) 78.3% (57.7–90.8) 65.2% (44.8–81.3) 82.8% (65.0–92.9) 83.3% (76.2–88.7)
9
c
84.1% (73.0–91.3) 84.0% (73.9–90.8) 87.0% (67.0–96.3) 73.9% (53.2–87.7) 89.7% (72.8–97.2) 84.1% (77.0–89.3)
SS-8 0.91 (0.85–0.96) 5 93.7% (84.3–98.0) 72.0% (60.9–81.0) 69.6% (48.9–84.6) 69.6% (48.9–84.6) 75.9% (57.6–88.1) 81.9% (74.6–87.5)
4
c
84.1% (73.0–91.3) 88.0% (78.5–93.8) 91.3% (72.0–98.8) 78.3% (57.7–90.8) 93.1% (77.0–99.2) 86.2% (79.4–91.1)
Validation:
PD vs. HC
(center B)
SS-16 0.91 (0.88–0.93) 10 83.3% (79.3–86.6) 82.0% (75.0–87.4) 82.6% (79.1–85.5)
SS-8 0.90 (0.88–0.93 5 85.3% (81.4–88.4) 83.3% (76.5–88.5) 84.7% (81.5–87.5)
Part A of the table: Pvalues report significances of comparisons of values in respective columns/groups versus PD within centers (A, B, and C) and are post hoc Bonferroni corrected for center A. Part B of the
table: Preferred cutoffs of predictive scores were determined by Youden’s index in the discovery cohort and, in a subgroup analysis, did not differ between sexes. SS-8 5subscore of the eight best-discriminating
odors (licorice, anise, mint, cinnamon, banana, pineapple, rose, and coffee).
a
Results represent means 6standard deviation; Pvalues calculated using Mann-Whitney’s U test.
b
Pvalue calculated using chi-square test.
c
Additional lower cutoffs were applied in the distinction versus DDs because a mildly decreased sense of smell had been reported in MSA, PSP, and ET patients
2,5
and our model was established in a comparison
of PD patients with HCs (discovery cohort).
MMSE, Mini–Mental State Examination; NA, not applicable.
ODOR IDENTIFICATION IN PD
Movement Disorders, Vol. 00, No. 00, 2016 3
patients who were reclassified (MSA, 1 case; PSP, 3
cases) during clinical follow-up had a normal olfactory
function at baseline according to the SS-16 and SS-8. In
a modeled general neurological service (PD prevalence:
91.8%), both the SS-16 and the SS-8 would yield PPVs
of >97%. In a specialized outpatient clinic (lower PD
prevalence 69.0% because of higher proportion of non-
PD parkinsonism), PPVs of around 90% would be
achieved (Supporting Table 2). To test the usefulness of
the SS-16 and the SS-8 as a screening method for early/
prodromal PD, we repeated the diagnostic accuracy
analyses after excluding patients with >3 years of dis-
ease duration, which did not alter the results (Supporting
Table 3). Furthermore, the 8 incident PD cases among
iRBD patients were predicted with the SS-16 and the SS-
8 with the same sensitivity of 100.0% (95% CI: 62.8–
100.0), specificity of 68.8% (95% CI: 44.2–86.1), PPV
of 61.5% (95% CI: 35.4–82.4), and NPV of 100.0%
(95% CI: 70.0–100.0).
Discussion
We found excellent diagnostic accuracy for the SS-
16 and a shortened test, the SS-8, in the distinction of
FIG. 1. Identification of individual odors in the study groups in the three different centers (A). Gray horizontal line indicates the probability of correctly
guessing an odor in the employed forced choice test. AUCs with 95% CIs as a function of combination of odors best predicting PD according to
the LASSO analysis in the various cohorts (B). The three horizontal lines in each graph represent the AUCs with 95% CIs of the full test used (SS-16
for the upper row and SS-12 for the lower row). The best eight discriminating odors derived from the full SS-16 were used for the SS-8 subscore
(licorice, anise, mint, cinnamon, banana, pineapple, rose, and coffee).
MAHLKNECHT ET AL
4Movement Disorders, Vol. 00, No. 00, 2016
PD not only from controls, but also from non-PD
tremor or atypical parkinsonism.
To the best of our knowledge, our study is the larg-
est study of olfactory testing ever performed in
patients with PD, related disorders, and controls com-
prising a total of 1,351 individuals. We employed a
sophisticated logistic regression analysis to determine
reduced sets of odors along the LASSO regularization
path in a discovery cohort. This variable selection
algorithm considers the statistical dependencies among
odor-specific olfactory impairments and minimizes
redundancy. Whereas the diagnostic performance in
identifying PD of the three, four, or five best-
discriminating odors was inferior to the whole SS-16,
the six best discriminating odors achieved accuracy
within the 95% CI of the AUCs of the entire set,
which was further improved by using a combination
of eight odors (but not beyond).
Short tests such as the SS-8 might be particularly
appealing for two purposes: First, in a clinical setting,
they might serve as an additional quick (approxi-
mately 3 minutes) and handy tool in the workup of
patients presenting with parkinsonism where clinicians
want to identify true PD cases with a high specificity
and predictivity. In our sample, the specificity for PD
was high (84% with the SS-16 and 88% with the SS-
8) combined with a high sensitivity (84%). When
modeling prevalences in a general neurological service
and a specialized movement disorders outpatient
clinic, the PPVs were high at 98% and 94%, respec-
tively. The usefulness of the SS-16 and SS-8 for ruling
out DDs is further supported by the analysis in par-
kinsonian patients with less than 3 years of disease
duration yielding a similar diagnostic accuracy as in
the whole sets. Indeed, all 4 patients in whom an ini-
tial diagnosis of PD was later changed to MSA or PSP
during follow-up had a normal olfactory function.
Second, a short olfactory test could be useful as a
highly sensitive screening tool in population-based
studies seeking to define cohorts at high risk for
PD.
3,24
Along these lines, we found a high sensitivity
of the SS-16 and SS-8 in identifying PD versus HCs in
the center A (92% and 94%) and center B (83% and
85%) validation cohorts combined with a good speci-
ficity of 82%. This excellent diagnostic accuracy
remained unchanged when only PD patients with less
than 3 years of disease duration were included. Fur-
thermore, the SS-16 and SS-8 accurately identified 8
incident PD cases from a previously described cohort
of 24 iRBD patients clinically followed for 6 years.
Whereas previous studies focused on even shorter
sets of three odors in the Sniffin’ Sticks or UPSIT,
9-13
in our analysis six to eight odors emerged as the
smallest number with equal performance as the entire
set. In line with previous evidence,
25
this argues
against the concept of selective anosmia in PD.
13
Also,
one must take into account that the nature of the Snif-
fin’ Sticks (and the UPSIT) as a forced-choice test bear-
ing an inherent 25% likelihood of a correct answer,
which limits the options of setting cutoffs in reduced
odor sets, possibly resulting in unsatisfactory specificity
and/or sensitivity. It should be noted that none of the
previous studies used independent validation samples,
which is a particular strength of our study.
However, there are limitations. Diagnoses of PD
and DDs were made according to clinical criteria
without pathological confirmation. Therefore, mis-
diagnosis cannot be ruled out. However, in center A,
patients with parkinsonism were followed up for at
least 2 years in order to reduce likelihood of misdiag-
noses. Furthermore, cultural differences may impact
on short olfactory tests to a greater extent compared
to longer sets, where a greater variety of odors might
balance such effects.
26
Nevertheless, given the repro-
ducibility shown in the external validation samples, it
is likely that diagnostic accuracy in other samples will
be similar.
To conclude, our analysis confirms that odor identi-
fication testing with the SS-16 is associated with excel-
lent accuracy in diagnosing PD and shows that it can
be shortened considerably without losing diagnostic
power. A shortened test of eight odors may be of sub-
stantial value in both a clinical setting assisting in the
distinction from frequent diagnostic mimics and in a
population-based setting for PD risk evaluation.
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MAHLKNECHT ET AL
6Movement Disorders, Vol. 00, No. 00, 2016
... Based on previous studies of integrated function, it is expected that the effects of aging are minimal. On the other hand, PD has been reported to decrease various cognitive functions as well as motor impairment (Reddy et al., 2002;Cools, 2006;Goldman and Weintraub, 2015;Mahlknecht et al., 2016;Huang et al., 2023), and has also been shown to reduce the integrated function of vision and olfactory (Honma et al., 2018a). Based on that previous study, it is likely that PD impairs the recalibration of ownership caused by vision and respiratory rhythm. ...
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Introduction Recalibration of body ownership perception occurs through an integration among multiple modalities. A recent study has shown that respiratory rhythm also causes the recalibration of ownership perception. However, the risk factors influencing the recalibration of ownership perception caused by vision-respiratory interaction remain unclear. In this study, focusing on aging and Parkinson’s disease (PD), we examined the effects of those risk factors on the recalibration. Methods By applying the rubber hand illusion (RHI), which temporarily alters ownership perception, and using a device that synchronizes the respiratory rhythm with the movement of a mannequin hand, we measured a change in ownership perception in RHI training by vision-respiratory interaction. The changed ownership was compared among the elderly healthy, PD, and young healthy groups. Results The results showed no difference in the changed ownership between the elderly healthy and PD groups, while the two groups decreased the change in the ownership perception compared to the young healthy group. Discussion The finding suggests that aging, not PD, related to the recalibration of ownership perception by vision-respiratory interaction. An anomaly in body perception due to aging may be associated with a mechanism in which respiratory rhythm affects the adaptation of body representations.
... This indicates that OL might be present in parkinsonisms other than Parkinson's disease [45]. However, both populations with PSP and populations with MSA seem to exhibit less-pronounced smell dysfunction compared to most PD patients [46]. Patients with PSP show a wide spectrum of severity of OL ranging from normosmia to levels as profound as those observed in idiopathic Parkinson's disease. ...
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Introduction: Atypical parkinsonisms (APs) present various symptoms including motor impairment, cognitive decline, and autonomic dysfunction. Olfactory loss (OL), being a significant non-motor symptom, has emerged as an under-evaluated, yet potentially valuable, feature that might aid in the differential diagnosis of APs. State of the art: The most pronounced OL is usually associated with Dementia with Lewy Bodies (DLB). While the view about the normosmic course of Multiple System Atrophy (MSA) remains unchanged, research indicates that mild OL may occur in a subset of patients with Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). This might be linked to the deposition of abnormal protein aggregates in the central nervous system. Clinical significance: The aim of this review is to discuss the role of OL and its degree and pattern in the pathogenesis and course of APs. Olfactory testing could serve as a non-invasive, quick screening tool to differentiate between APs and project disease progression. Future directions: There is a need for further evaluation of this topic. This may lead to the development of standardized olfactory testing protocols that could be implemented in clinical practice, making differential diagnosis of APs more convenient. Understanding differences in the sense of smell could create an avenue for more targeted therapeutic strategies.
... Finally, there is a need to longitudinally investigate at what stage the onset of time cognitive dysfunction and learning disability occurs. Currently, many researchers are focusing on decreased olfactory ability and sleep disorder as precursor symptoms of PD (51)(52)(53). Longitudinal studies of the onset timing of disorder might suggest that time cognition is a novel biomarker for predicting PD onset. Furthermore, the degree of time cognitive learning may also vary depending on the stage of progression of the main disease, and then it may be an important perspective in terms of early detection of disease and effectiveness of rehabilitation. ...
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Time cognition is an essential function of human life, and the impairment affects a variety of behavioral patterns. Neuropsychological approaches have been widely demonstrated that Parkinson’s disease (PD) impairs time cognitive processing. Many researchers believe that time cognitive deficits are due to the basal ganglia, including the striatum or subthalamic nucleus, which is the pathomechanism of PD, and are considered to produce only transient recovery due to medication effects. In this perspective, we focus on a compensatory property of brain function based on the improved time cognition independent of basal ganglia recovery and an overlapping structure on the neural network based on an improved inhibitory system by time cognitive training, in patients with PD. This perspective may lead to restoring multiple functions through single function training.
... Proposed biomarkers include clinical, imaging, biofluidic-base, and inflammation-related biomarkers for preclinical, prodromal, and clinical stages [9,10]. Some of the proposed tools and methods for the early detection of PD are based on analysing voice disorders [11,12], handwriting [13], olfactory testing [14], and accelerometery data [15]. Other proposed solutions based on the use of Artificial Intelligence include convolutional neural networks for eye tracking and facial expression analysis [16], Machine Learning-assisted speech analysis [17], and deep learning models for various modalities such as brain analysis and motion symptoms [18]. ...
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To date, clinical expert opinion is the gold standard diagnostic technique for Parkinson’s disease (PD), and continuous monitoring is a promising candidate marker. This study assesses the feasibility and performance of a new wearable tool for supporting the diagnosis of Parkinsonian motor syndromes. The proposed method is based on the use of a wrist-worn measuring system, the execution of a passive, continuous recording session, and a computation of two digital biomarkers (i.e., motor activity and rest tremor index). Based on the execution of some motor tests, a second step is provided for the confirmation of the results of passive recording. In this study, fifty-nine early PD patients and forty-one healthy controls were recruited. The results of this study show that: (a) motor activity was higher in controls than in PD with slight tremors at rest and did not significantly differ between controls and PD with mild-to-moderate tremor rest; (b) the tremor index was smaller in controls than in PD with mild-to-moderate tremor rest and did not significantly differ between controls and PD patients with slight tremor rest; (c) the combination of the said two motor parameters improved the performances in differentiating controls from PD. These preliminary findings demonstrate that the combination of said two digital biomarkers allowed us to differentiate controls from early PD.
... Receiver operating curve (ROC) analysis pointed out that; SST variables have a high sensitivity and specificity in differentiating between TDPD and ET patients, which means that; olfactory testing is a feasible easily accessible method to discriminate between these disorders, and could help neurologist when higher functional brain imaging modalities not available. Another study [37] reported a high sensitivity of the the SS-16 and a shortened test, the SS-8, in the distinction of PD from non-PD tremor, they reported the identification test which consume only 3 min is rapid cheap clinical tool for that purpose. Our results showed that not only the identification but all the SST are of high clinical value in discriminating TDPD disease patients from ET patients. ...
... The high identification accuracy of garlic may be attributed to its volatile sulfur compound [23], which humans are highly sensitive to and thus, are more easily identified. The odor with the lowest recognition accuracy was that of leather (33%), contradictory to the results of Chen et al.'s [19] and Mahlknecht et al.'s studies [24], in which apples had the lowest identification accuracy. Discrepancies in odorant exposure, such as cultural backgrounds and personal life histories, could account for the conflicts between studies. ...
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To investigate whether glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and 12 cytokines can serve as serum biomarkers of olfactory identification dysfunction in patients with Parkinson’s disease (PD). GFAP and NFL levels were measured in 75 patients with PD and 36 healthy controls (HCs). The levels of 12 cytokines were assayed in 41 patients with PD. The 16-item Sniffin’ Sticks test and the Mini-Mental State Examination (MMSE) were used to assess olfactory identification ability and cognitive function, respectively. Linear regression models were applied to control for confounding effects. Receiver operating characteristic curves were used to examine the diagnostic accuracy of serum NFL, GFAP, and interleukin-6 (IL-6) levels. The cut-off value for the SS-16 test in diagnosing dysosmia was equal to 9.5 points. Serum GFAP levels were higher in patients with PD with olfactory identification dysfunction than in those without. GFAP, NFL, and IL-6 levels were correlated with SS-16 scores. Moreover, combining these three biomarkers yielded the best-fitting model for distinguishing patients with PD with or without dysosmia. We found a prominent indirect effect of GFAP on MMSE scores through its contribution to SS-16 scores. GFAP, NFL, and IL-6 can serve as serum biomarkers for olfactory identification dysfunctions in PD. We inferred that astrogliosis might promote the occurrence of dysosmia by releasing proinflammatory factors and causing neuronal damage and may indirectly impair cognition through its effect on olfactory function.
... As expected, odor identification in the PD group was significantly lower than HCs. This finding has agreed with earlier reports [64][65][66] and shows our patients suffer from the olfactory deficit. However, there was no correlation between our PD patients' cognitive profile and their olfactory test outcomes. ...
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Background: Non-motor symptoms (NMS) such as cognitive impairment are among common presentations in patients with Parkinson's disease (PD). In parallel with motor symptoms, these impediments can affect PD patients' quality of life. However, cognitive impairment has received less attention in early PD. On the other hand, the relationship between olfactory symptoms and cognitive impairment is unclear in early PD. Considering the importance of accurate and timely assessment of cognitive function in PD patients using readily available/validated tests, this study has employed the Cambridge Brain Sciences-Cognitive Platform (CBS-CP) as a computer-based tool to assess cognitive presentations in early PD patients. Methods: Thirty-four eligible males and females were assigned to PD and healthy controls (HCs). The cognitive performance was assessed using CBS-CP and Mini-Mental State Examination (MMSE), and olfactory function was measured through the standardized olfactory Quick Smell test (QST). Results: PD patients had poorer performance in all CBS-CP tasks, including short-term memory, attention, and reasoning domains than HCs. Meanwhile, the verbal domain task scores showed no significant difference between groups. PD MMSE results were in the normal range (mean=26.96), although there was a significant difference between the PD and HCs groups (P = 0.000). Our results revealed no correlation between cognitive impairment and olfactory function in PD patients. Conclusion: Given the widely studied features of CBS-CP and its reliability across published evidence, CBS-CP appears to be a suitable measurement to evaluate cognitive impairment in early PD with normal MMSE scores. It seems cognitive and olfactory impairments are independent in early PD. Data availability statement: The datasets generated during the current study are available from the corresponding author upon reasonable request.
... Thus, ODs appear with a greater occurrence than the main motor symptom, i.e. resting tremor (around 70 to 80%) [11], although a majority of patients are unaware of their olfactory loss [12,13]. ODs are clinically significant in the early stage of PD [14,15] and have been reported for a long time to suggest idiopathic PD [16][17][18][19][20], to serve as a diagnostic marker [21][22][23], and to distinguish PD from Progressive Supranuclear Palsy and essential tremor [24,25]. Within the spectrum of parkinsonism, ODs are not specific to PD, but have also been reported in multiple system atrophy (MSA) patients, although ODs appear to differentiate between vascular parkinsonism and PD and are absent in parkin disease [26,27]. ...
Article
Deep brain stimulation (DBS) is a surgical therapy typically applied in Parkinson's disease (PD). The efficacity of DBS on the control of motor symptoms in PD is well grounded while the efficacity on non-motor symptoms is more controversial, especially on olfactory disorders (ODs). The present review shows that DBS does not improve hyposmia but can affect positively identification/discrimination scores in PD. The functional hypotheses suggest complex mechanisms in terms of cerebral connectivity and neurogenesis process which could act indirectly on the olfactory bulb and olfactory pathways related to specific cognitive olfactory tasks. The functional hypotheses also suggest complex mechanisms of cholinergic neurotransmitter interactions involved in these pathways. Finally, the impact of DBS on general cognitive functions in PD could also be beneficial to identification/discrimination tasks in PD.
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Background: Reduced olfaction is a common feature of patients with typical Parkinson disease (PD). We sought to develop and validate a simplified smell test as a screening tool to help identify PD patients and explore its differentiation from other forms of parkinsonism. Methods: We used the Sniffin' Sticks Identification Test (SST-ID) and the University of Pennsylvania Smell Identification Test (UPSIT), together with data from three case-control studies, to compare olfaction in 301 patients with PD or dementia with Lewy bodies (DLB) to 36 subjects with multiple system atrophy (MSA), 32 individuals with progressive supranuclear palsy (PSP) and 281 neurologically healthy controls. Individual SST-ID and UPSIT scents were ranked by area under the receiver operating characteristic curve (AUC) values for group classification, with 10-fold cross-validation. Additional rankings were generated by leveraging results from eight published studies, collectively including 5,853 unique participants. Lead combinations were further validated using (semi-)independent datasets. An abbreviated list of scents was generated based on those shared by SST-ID and UPSIT. Findings: We made the following five observations: (i) PD and DLB patients generally had worse olfaction than healthy controls, as published, with scores for MSA and PSP patients ranking as intermediate. (ii) SST-ID and UPSIT scents showed distinct discriminative performances, with the top odorants (licorice, banana, clove, rose, mint, pineapple and cinnamon) confirmed by external evidence. (iii) A subset of only seven scents demonstrated a similar performance to that of the complete 16-scent SST-ID and 40-scent UPSIT kits, in both discovery and validation steps. Seven scents distinguished PD/DLB subjects from healthy controls with an AUC of 0.87 (95%CI 0.85-0.9) and PD/DLB from PSP/MSA patients with an AUC of 0.73 (95%CI 0.65-0.8) within the three cohorts (n=650). (iv) Increased age was associated with a decline in olfaction. (v) Males generally scored lower than females, although this finding was not significant across all cohorts. Interpretation: Screening of subjects for typical Parkinson's-associated hyposmia can be carried out with a simplified scent identification test that relies on as few as seven specific odorants. There, the discrimination of PD/DLB subjects vs. age-matched controls is more accurate than that of PD/DLB vs. PSP/MSA patients. Funding: This work was supported by: Parkinson Research Consortium; uOttawa Brain & Mind Research Institute; and the Aligning Science Across Parkinson's Collaborative Research Network.
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Olfactory function assessment is an important screening tool and also may differentiate Parkinson's disease (PD) patients from other parkinsonisms, including nondegenerative ones, such as, normal pressure hydrocephalus, vascular, drug induced, or infectious parkinsonism. Several authors in different countries have reported various sets of odors that best differentiate between these conditions. It is debated if distinctive patterns of "restrictive" or "selective" hyposmia in PD may be affected by cultural aspects. To compare the olfactory identification function in PD across different countries, we analyzed Sniffin' Sticks identification task results between 112 PD patients from Argentina and previously reported data of PD patients from Brazil (106 patients), the Netherlands (400 patients), Germany (40 patients), China (110 patients), and Sri Lanka (89 patients). Categorical principal component analysis (CATPCA) was performed to find components reflecting groups of odors similarly perceived across subjects. CATPCA analysis found 2 components for each group which shared 10 out of 16 odors amongst each other. We found that only the shared items of component 2 (orange, mint, banana, garlic, coffee, cloves, and fish) showed uniform results across all of the included countries, whereas variations in component 1 (licorice, turpentine, and apple) were attributed mostly to differences across control groups.
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With advances in knowledge disease, boundaries may change. Occasionally, these changes are of such a magnitude that they require redefinition of the disease. In recognition of the profound changes in our understanding of Parkinson's disease (PD), the International Parkinson and Movement Disorders Society (MDS) commissioned a task force to consider a redefinition of PD. This review is a discussion article, intended as the introductory statement of the task force. Several critical issues were identified that challenge current PD definitions. First, new findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. Second, the increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. Third, there is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. Fourth, the recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. Finally, there is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration. © 2014 International Parkinson and Movement Disorder Society
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Signal abnormalities of the substantia nigra and the olfactory tract detected either by diffusion tensor imaging, including measurements of mean diffusivity, a parameter of brain tissue integrity, and fractional anisotropy, a parameter of neuronal fibre integrity, or transcranial sonography, were recently reported in the early stages of Parkinson's disease. In this study, changes in the nigral and olfactory diffusion tensor signal, as well as nigral echogenicity, were correlated with clinical scales of motor disability, odour function and putaminal dopamine storage capacity measured with 6-[(18)F] fluorolevodopa positron emission tomography in early and advanced stages of Parkinson's disease. Diffusion tensor imaging, transcranial sonography and positron emission tomography were performed on 16 patients with Parkinson's disease (mean disease duration 3.7 ± 3.7 years, Hoehn and Yahr stage 1 to 4) and 14 age-matched healthy control subjects. Odour function was measured by the standardized Sniffin' Sticks Test. Mean putaminal 6-[(18)F] fluorolevodopa influx constant, mean nigral echogenicity, mean diffusivity and fractional anisotropy values of the substantia nigra and the olfactory tract were identified by region of interest analysis. When compared with the healthy control group, the Parkinson's disease group showed significant signal changes in the caudate and putamen by 6-[(18)F] fluorolevodopa positron emission tomography, in the substantia nigra by transcranial sonography, mean diffusivity and fractional anisotropy (P < 0.001, P < 0.01, P < 0.05, respectively) and in the olfactory tract by mean diffusivity (P < 0.05). Regional mean diffusivity values of the substantia nigra and the olfactory tract correlated significantly with putaminal 6-[(18)F] fluorolevodopa uptake (r = -0.52, P < 0.05 and r = -0.71, P < 0.01). Significant correlations were also found between nigral mean diffusivity values and the Unified Parkinson's Disease Rating Scale motor score (r = -0.48, P < 0.01) and between mean putaminal 6-[(18)F] fluorolevodopa uptake and the total odour score (r = 0.58; P < 0.05) as well as the Unified Parkinson's Disease Rating Scale motor score (r = -0.53, P < 0.05). This study reports a significant association between increased mean diffusivity signal and decreased 6-[(18)F] fluorolevodopa uptake, indicating that microstructural degradation of the substantia nigra and the olfactory tract parallels progression of putaminal dopaminergic dysfunction in Parkinson's disease. Since increases in nigral mean diffusivity signal also correlated with motor dysfunction, diffusion tensor imaging may serve as a surrogate marker for disease progression in future studies of putative disease modifying therapies.
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This article describes research criteria and probability methodology for the diagnosis of prodromal PD. Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Given the lack of clear neuroprotective/disease-modifying therapy for prodromal PD, these criteria were developed for research purposes only. The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty. Certainty estimates rely upon calculation of an individual's risk of having prodromal PD, using a Bayesian naïve classifier. In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios. This diagnostic information combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing. In order to be included, diagnostic markers had to have prospective evidence documenting ability to predict clinical PD. They include motor and nonmotor clinical symptoms, clinical signs, and ancillary diagnostic tests. These criteria represent a first step in the formal delineation of early stages of PD and will require constant updating as more information becomes available. © 2015 International Parkinson and Movement Disorder Society.
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This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances. © 2015 International Parkinson and Movement Disorder Society.
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We have reviewed the clinical and pathological diagnoses of 143 cases of parkinsonism seen by neurologists associated with the movement disorders service at The National Hospital for Neurology and Neurosurgery in London who came to neuropathological examination at the United Kingdom Parkinson's Disease Society Brain Research Centre, over a 10-year period between 1990 and the end of 1999. Seventy-three (47 male, 26 female) cases were diagnosed as having idiopathic Parkinson's disease (IPD) and 70 (42 male, 28 female) as having another parkinsonian syndrome. The positive predictive value of the clinical diagnosis for the whole group was 85.3%, with 122 cases correctly clinically diagnosed. The positive predictive value of the clinical diagnosis of IPD was extremely high, at 98.6% (72 out of 73), while for the other parkinsonian syndromes it was 71.4% (50 out of 70). The positive predictive values of a clinical diagnosis of multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) were 85.7 (30 out of 35) and 80% (16 out of 20), respectively. The sensitivity for IPD was 91.1%, due to seven false-negative cases, with 72 of the 79 pathologically established cases being diagnosed in life. For MSA, the sensitivity was 88.2% (30 out of 34), and for PSP it was 84.2% (16 out of 19). The diagnostic accuracy for IPD, MSA and PSP was higher than most previous prospective clinicopathological series and studies using the retrospective application of clinical diagnostic criteria. The seven false-negative cases of IPD suggest a broader clinical picture of disease than previously thought acceptable. This study implies that neurologists with particular expertise in the field of movement disorders may be using a method of pattern recognition for diagnosis which goes beyond that inherent in any formal set of diagnostic criteria.
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Absence of a hyperintense, ovoid area within the dorsolateral border of the otherwise hypointense pars compacta of the substantia nigra (referred to as dorsolateral nigral hyperintensity) on iron-sensitive high-field magnetic resonance imaging sequences seems to be a typical finding for patients with Parkinson's disease (PD). This study was undertaken to evaluate the diagnostic value of the dorsolateral nigral hyperintensity in a cohort of patients with neurodegenerative parkinsonism including PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) as well as healthy controls using high-field susceptibility-weighted imaging (SWI) at 3.0 Tesla (T). Absence of dorsolateral nigral hyperintensity was assessed on visual inspection of anonymized 3.0T SWI scans in a case-control study including 148 patients with neurodegenerative parkinsonism (PD: n = 104; MSA: n = 22; PSP: n = 22) and 42 healthy controls. Dorsolateral nigral hyperintensity was absent unilaterally in all patients with MSA or PSP, in 83 of 90 patients with PD, but only in one of the healthy controls resulting in an overall correct classification of 95.2% in discriminating neurodegenerative parkinsonism from controls in the per-protocol analysis. Overall correct classification was 93.2% in the intent-to-diagnose analysis, including also SWI scans with poor quality (12.1% of all scans) for nigral evaluation. Visual assessment of dorsolateral nigral hyperintensity on high-field SWI scans may serve as a new simple diagnostic imaging marker for neurodegenerative parkinsonian disorders. © 2015 International Parkinson and Movement Disorder Society. © 2015 International Parkinson and Movement Disorder Society.
Article
The aim of the present study was to determine the predictive value of olfactory dysfunction for the early development of a synuclein-mediated neurodegenerative disease in subjects with idiopathic REM sleep behavior disorder (iRBD) over an observational period of 5 years. Thirty-four patients with polysomnography-confirmed iRBD underwent olfactory testing using the entire Sniffin' Sticks test assessing odor identification, odor discrimination, and olfactory threshold. Patients with iRBD were prospectively followed up over a period of 4.9 ± 0.3 years (mean ± SD). The diagnosis of neurodegenerative diseases was based on current clinical diagnostic criteria. After 2.4 ± 1.7 years (mean ± SD), 9 patients (26.5%) with iRBD developed a Lewy body disease (6 Parkinson disease and 3 dementia with Lewy bodies). The entire Sniffin' Sticks test and the identification subtest had the same overall diagnostic accuracy of 82.4% (95% confidence interval: 66.1%-92.0%) in predicting conversion. The relative risk for a Lewy body disease in the lowest tertile of olfactory function was 7.3 (95% confidence interval: 1.8-29.6) compared with the top 2 tertiles. Assessment of olfactory function, particularly odor identification, may help to predict the development of a Lewy body disease in patients with iRBD over a relatively short time period and thus to identify patients suitable for future disease modification trials. © 2015 American Academy of Neurology.