Olfactory dysfunction in LRRK2 G2019S
K. Stanley, BS
C. Wang, PhD
M. San Luciano, MD
V. Shanker, MD
A. Hunt, DO
L. Severt, MD
D. Raymond, MS
L.J. Ozelius, PhD
R.B. Lipton, MD
S.B. Bressman, MD
Background: Olfactory dysfunction is an established nonmotor feature of idiopathic Parkinson
disease (PD), which may precede disease onset. Olfaction is likely disturbed in patients with PD
with leucine-rich repeat kinase (LRRK2) G2019S mutations, although the degree of impairment is
debated. It is also unclear whether mutation carriers who have not yet manifested with PD have
Methods: Thirty-one subjects with LRRK2 G2019S mutation–related PD (PD-manifesting carri-
ers [PD-MC]), 30 subjects with PD without mutations (PD noncarriers [PD-NC]), 28 mutation car-
rier family members (nonmanifesting carriers [NMC]), and 46 controls completed the University of
Pennsylvania Smell Identification Test (UPSIT). Generalized estimating equations were applied to
determine whether olfactory score was associated with PD and LRRK2 mutation status.
Results: As expected, having PD was associated with impaired olfaction regardless of LRRK2
mutation status. More importantly, however, impaired olfaction was increased overall in LRRK2
carriers both with and without PD, though the impairment was only present in a subset of NMCs.
Compared to controls, the mean score was lower among NMC (difference ? ?3.518, p ? 0.006),
MC (difference ? ?7.677, p ? 0.0001), and idiopathic PD (PD-NC) (difference ? ?13.810, p ?
0.0001). Olfaction was better among MC (PD-MC) than non-LRRK2 PD (PD-NC) (difference ?
6.13, p ? 0.0012). Group differences from the continuous analysis were maintained in dichoto-
mous analysis stratifying at 15th percentile for age and gender.
Conclusion: Olfaction is impaired in LRRK2 G2019S–mutation related PD, although less overall
than other PD. Further, olfaction is impaired in a subset of LRRK2 NMC, suggesting that olfaction
may be a marker for development of PD in this group, and that longitudinal studies are warranted.
CI ? confidence interval; EAS ? Einstein Aging Study; MC ? manifesting carrier; NC ? noncarriers; NMC ? nonmanifesting
carrier; PD ? Parkinson disease; UPDRS ? Unified Parkinson’s Disease Rating Scale; UPSIT ? University of Pennsylvania
Smell Identification Test.
Parkinson disease (PD) due to mutations in the LRRK2 gene appears to more closely mimic
idiopathic PD than any other genetic etiology.1Yet there are still gaps and uncertainty in our
knowledge of LRRK2 clinical expression. For example, there is controversy regarding the clini-
cal course of LRRK2 PD and whether progression is similar or less rapid compared with
idiopathic PD.2–4The range and severity of nonmotor features associated with LRRK2 muta-
tions is also not well-defined. Several studies suggest that olfactory disturbance is a feature of
LRRK2 PD3,5–8but the degree of the impairment is debated. Finally, it is uncertain whether
carriers who have not yet developed PD have abnormal olfaction,6,7and whether this may be an
endophenotype or trait of carrying the mutated LRRK2 gene.
From the Department of Neurology (R.S.-P., K.S., M.S.L., V.S., A.H., L.S., D.R., S.B.B.), Beth Israel Medical Center, New York; Departments of
Neurology (R.S.-P., V.S., R.B.L., S.B.B.) and Epidemiology and Social Medicine (C.W.), Albert Einstein College of Medicine, Bronx; and
Departments of Genetics and Genomic Sciences and Neurology (L.J.O.), Mount Sinai School of Medicine, New York, NY.
Study funding: Supported by the Michael J Fox Foundation (R.S.-P., S.B.B.), the NIH/NINDS (K23NS047256, R.S.-P.), the Thomas Hartman
Foundation for Parkinson’s Research, and NIH/NIA (AG03949, R.B.L.).
Disclosure: Author disclosures are provided at the end of the article.
Editorial, page 310
Address correspondence and
reprint requests to Dr. Rachel
Saunders-Pullman, The Alan and
Barbara Mirken Department of
Neurology, Beth Israel Medical
Center, 10 Union Square East,
Suite 5J, New York, NY 10003
Copyright © 2011 by AAN Enterprises, Inc.
Hyposmia is a common nonmotor feature
of PD, present in 70%–100% of subjects with
PD9,10and may discriminate PD from atypi-
cal forms such as vascular parkinsonism and
corticobasal degeneration.11–13Loss of neu-
rons and Lewy body deposition are also noted
in the anterior olfactory bulb in PD.14Olfac-
tion has been reported as normal in some ge-
netic etiologies of parkinsonism, such as that
due to parkin mutations,15but is abnormal
in PINK1 and glucocerebrosidase-related
PD.16–18However, the association with olfac-
tion in LRRK2 PD is less clear: olfaction has
been reported as normal,19not as significantly
affected, or as consistently impaired as in idio-
pathic PD.3,5–8Olfactory loss may precede
clinical PD by at least 4 years,20and thus may
be a marker of developing PD. Reports of ol-
faction in LRRK2 mutation carriers without
PD, a group that is at increased risk of devel-
oping PD, are both limited and conflicting.6,7
In order to systematically examine whether ol-
faction is affected in LRRK2 PD compared
with idiopathic PD, and determine whether
olfaction is impaired in mutation carriers who
have not yet manifested PD, we studied
LRRK2 G2019S mutation carriers with
PD-MC (manifesting carriers [MC]), unaf-
fected family members with LRRK2 muta-
tions (nonmanifesting carriers [NMC]),
subjects with PD without LRRK2 mutations
(PD noncarriers, PD-NC), and healthy
controls without a family history of PD
METHODS Sixty-one subjects with PD (31 with LRRK2
G2019S mutations [PD-MC] and 30 without [PD-NC]), 28
mutation carrier family members (NMC), and 46 controls were
recruited from parent studies of Genetics and PD at Beth Israel
Medical Center and the Einstein Aging Study (EAS) at Albert
Einstein College of Medicine. At Beth Israel, all study subjects
were systematically examined by movement disorders specialists.
A diagnostic checklist was completed, and only those subjects
rated as having met stringent diagnostic criteria for PD21were
included. One family member who was determined to have PD
was not diagnosed prior to the examination, and is included
in the PD-MC group. Family members with G2019S muta-
tions as well as spouse and laboratory controls without a fam-
ily history of PD were included. At the EAS, formal
neurologic evaluation including completion of the Unified
Parkinson’s Disease Rating Scale (UPDRS)22was performed
by a physician; for this study, a subset of elderly controls
without parkinsonian features and with a Clinical Dementia
Rating Scale score of less than 1 were included. Any potential
subject who had a known respiratory tract infection or active
allergies was also excluded from the study.
fication Test (UPSIT) was self-administered by using standard 40-
odor identification23either at the time of the visit or at the subject’s
home, and returned by mail. Subjects were instructed to choose a
responses were excluded from the analysis.
DNA was available from blood or buccal swab drawn at the
parent study. LRRK2 genotyping was performed as previously
described.24All subjects were blinded to their mutation status
except for 2 mutation carriers with PD and one nonmanifesting
mutation carrier who had undergone clinical genetic testing.
Demographic characteristics and clinical scores among
groups were summarized with descriptive statistics. Raw UPSIT
scores were calculated as the number of correct identifications,
ranging from 0 to 40, with 40 representing perfect olfaction.
Analysis was performed first on the raw UPSIT scores as the
primary outcome. Scores were also categorized using normative
data for age and gender as previously reported by Doty,25with a
dichotomous cut at the 15th percentile.26Generalized estimating
equations (GEE) were applied to account for the correlations
among measurements of subjects from the same family and to
compare continuous UPSIT scores among the different groups,
adjusting for age and gender, with a logistic link for the dichoto-
mized UPSIT score. Analyses were performed using SAS 9.1
(SAS Institute Inc., Cary, NC).
Standard protocol approvals, registrations, and patient
consents. The study procedures were approved by the respec-
tive internal review boards at Beth Israel Medical Center and
Albert Einstein College of Medicine, and all subjects gave in-
RESULTS Demographic and clinical features are
shown in the table. The non-LRRK2 PD (PD-NC)
and MC (PD-MC) groups did not differ by age, du-
ration of disease, UPDRS score at time of visit, or
current or prior smoking. The NMC did not differ
compared with controls in regards to age, gender, or
current and prior smoking. However, compared with
the controls, those with PD were older (p ? 0.024).
The MC and the NMC were not different in age,
gender, or smoking status.
Analysis of continuous UPSIT scores is shown in
the table and in the figure. As anticipated, older age
was associated with lower UPSIT scores (worse olfac-
tion, p ? 0.0001). Prior smoking and gender were
not associated with worse olfaction. In the GEE
model adjusting for age, gender, and taking family
relationship into account, both PD and LRRK2 PD
as well as carrying the LRRK2 mutation without
manifesting symptoms were associated with worse ol-
faction: compared to controls, the mean score was
lower among NMC (mean estimate of difference ?
?3.518, 95% confidence interval [CI] ?6.004,
?1.03, p ? 0.006), PD-MC (difference ? ?7.677,
95% CI ?10.507, ?4.846, p ? 0.0001) and
PD-NC (difference ? ?13.810, 95% CI ?16.824,
?10.795, p ? 0.0001) as well as all PD (PD-NC
Neurology 77July 26, 2011
and PD-MC combined) (difference ? ?8.984, 95%
CI ?11.512, ?6.457, p ? 0.0001).
Olfaction was better among PD-MC than non-
LRRK2 PD (PD-NC) (difference ? 6.13, 95% CI
2.422, 9.845, p ? 0.0012).
While harboring the G2019S mutation was asso-
ciated with lower scores among both NMC and PD-
MC, the PD-MC group had a worse mean score than
NMC (difference ? ?4.159, 95% CI ?7.943,
?0.376, p ? 0.0312). The expected interaction be-
tween harboring the LRRK2 mutation and having
PD (p ? 0.0001) was observed.
In the analysis of categorical UPSIT scores (based
on age and gender normative data at the 15th per-
centile; table), group differences which were noted
for the raw UPSIT score were maintained in the di-
chotomous analysis: LRRK2 PD subjects (PD-MC)
were more likely to be hyposmic than both NMC
(OR ? 3.05, p ? 0.032) and controls (OR ? 25.69,
p ? 0.0001), but less likely than non-LRRK2 PD
subjects (PD-NC) (OR ? 0.27, p ? 0.034); LRRK2
NMC were more likely to be hyposmic than controls
(OR ? 8.44, p ? 0.004).
DISCUSSION Olfactory dysfunction is established
as a common nonmotor feature of PD9,27,28and there
is a correlation between olfactory dysfunction and
[99mTc] TRODAT-1 SPECT dopamine trans-
porter density.29Screening of first-degree relatives
who have not developed motor features of PD, but
have abnormal dopamine metabolism on PET, sug-
gests that impairment in olfaction precedes clinical
PD and is associated with dopaminergic cell loss.30–32
In this, the largest series of olfaction in LRRK2-
related PD studied to date, our data support that
olfactory disturbances, while less severe than idio-
pathic PD, are also a prominent feature of LRRK2
G2019S–related PD.33Further, our data suggest that
olfactory dysfunction is a feature of carrying the
LRRK2 G2019S mutation that may occur without
manifesting motor features. Because olfactory
disturbances are not as severe in NMC overall
compared to MC, and because this was a cross-
sectional study, it is unclear whether all NMC
with olfactory disturbances will evolve to develop
PD or whether they represent an intermediate en-
dophenotype that is not an immediate precursor
to development of PD.
The pathophysiologic basis of LRRK2 PD is still
not well understood: most autopsy reports demon-
strate ?-synuclein deposition with Lewy bodies as
well as nigral degeneration.6,34However, a range of
pathology is noted, with few cases demonstrating ni-
FigureKernel density plot demonstrating distribution of University of
Pennsylvania Smell Identification Test (UPSIT) scores in
manifesting carriers, Parkinson disease (PD), nonmanifesting
carriers, and controls
TableClinical features and UPSIT scores
(n ? 30)
(n ? 31)
LRRK2? NMC (n ? 28)Controls (n ? 46)
Age at examination, y,
mean ? SD (range)
63.4 ? 7.8 (48–77) 64.7 ? 9.8 (33–81)58.0 ? 22.4 (18–84) 57.9 ? 16.7 (25–99)
Gender, % (n) men
56.7 (17/30) 48.4 (15/31)46.4 (13/28)48.8 (22/46)
Current smoker, % (n)
3.45 (1/30)3.23 (1/31)3.85 (1/28)0
Past smoker, % (n)
37.9 (11/29)35.5 (11/31)30.8 (8/28) 30.4 (14/46)
PD duration, y, mean ? SD
9.3 ? 5.5 (2–21) 9.9 ? 6.7 (0–29)——
Motor UPDRS, mean ? SD
13.1 ? 9.4 (3–48)12.3 ? 10.9 (0–45)——
Continuous UPSIT scores,
mean ? SD (range)
18.8 ? 8.05 (5–36)24.8 ? 7.08 (9–38)30.1 ? 7.55 (10–39)33.6 ? 3.82 (18–39)
(<15th %ile), % (n)
83.3 (25/30)58.1 (18/31)35.7 (10/28)6.5 (3/46)
Abbreviations: PD-MC ? PD subject manifesting carrier of LRRK2 G2019S mutation; NMC ? nonmanifesting carrier; PD-
NC ? Parkinson disease, not G2019S carrier; UPDRS ? Unified Parkinson’s Disease Rating Scale; UPSIT ? University of
Pennsylvania Smell Identification Test.
Neurology 77July 26, 2011
gral degeneration in isolation35and others showing
tau inclusions.36In idiopathic PD, Lewy bodies and
Lewy neurites are noted in the olfactory bulb; fur-
ther, olfactory pathology is thought to occur as an
early or initial event according to the staging schema
for PD progression proposed by Braak et al.37In the
limited LRRK2 cases reported, ?-synuclein accumu-
lation in the rhinencephalon was shown in 4 cases of
G2019S mutation PD6and Lewy body deposition in
the olfactory bulb was demonstrated in one LRRK2
Y1699C mutation case.19These findings suggest that
the effects of mutant LRRK2 include olfactory pa-
thology, at least in a subset of carriers. Hence abnor-
mal olfaction noted in our unaffected mutation
carriers could represent the first stage in progression
to PD. However, the temporal characteristics of
LRRK2-related pathology are not established and
may not follow Braak’s staging schema. Evaluation of
other nonmotor features, including transcranial
sonography, and functional imaging and longitudi-
nal follow-up will help determine whether olfactory
involvement is necessarily part of inexorable pro-
gression of PD pathology or may represent a more
restricted gene effect.
Similar to PINK117and glucocerebrosidase-
associated PD,16,18but unlike PD due to parkin mu-
tations,15most8but not all19LRRK2 mutation studies
support the idea that olfaction is impaired in this
genetic form.8While the degree of olfactory pathol-
ogy has not been formally quantified in PD and
LRRK2 PD, our clinical data support the notion that
LRRK2 pathology may not be as extensive. A meta-
analysis of LRRK2 mutation subjects with olfactory
testing demonstrated that only 51% of LRRK2
G2019S mutation patients had significant olfactory
loss.3By virtue of the study design, however, LRRK2
cases could not be readily compared with controls or
other PD cases. Whereas this suggests better olfac-
tion than in idiopathic PD, it also highlights the
methodologic concerns about how to rate olfactory
abnormalities, and whether these should be consid-
ered relative to population norms, or whether each
research group reporting olfactory scores needs to de-
velop a large control sample.
Several reports have analyzed G2019S family
members, with heterogenous results.6–8Studies to
compare olfaction between NMCs and family mem-
bers who are noncarriers are currently underway and
should help determine whether olfactory disturbance
segregates with LRRK2 or whether it represents an
intrafamilial abnormality, suggesting other possibly
modifying PD genes.
A potential limitation of our study is that while
we have sampled one of the largest groups of NMCs,
including elderly NMCs, we did not have a large
control sample for every decade and gender. Hence,
we chose to report both continuous data compared
with our laboratory controls as well as categorical
normative data obtained through studies of 3,928
(1,819 men and 2,109 women) US controls.25
By demonstrating a difference between nonmani-
festing carriers and controls, we suggest that in a sub-
set of LRRK2 mutation carriers, UPSIT may identify
nonmotor features of preclinical PD. However, we
did not have enough NMCs to define subgroups;
only 35% of NMCs fell below the 15th percentile for
age and gender and thus some carriers may not have
olfactory disturbances or may have only minimal ol-
factory changes. Longitudinal studies are necessary to
determine the temporal relationship between olfac-
tion and the development of motor signs.28,32It is
hoped that better understanding of motor and non-
motor features of LRRK2 PD will shed light on the
pathophysiology of this genetic PD subtype.
Dr. Saunders-Pullman: drafting/revising the manuscript, study concept or
design, analysis or interpretation of data, acquisition of data, statistical
analysis, study supervision, obtaining funding. K. Stanley: drafting/
revising the manuscript, analysis or interpretation of data, acquisition of
data, statistical analysis, study supervision. Dr. Wang: drafting/revising
the manuscript, analysis or interpretation of data, statistical analysis. Dr.
San Luciano: drafting/revising the manuscript, analysis or interpretation
of data, acquisition of data, statistical analysis. Dr. Shanker: drafting/
revising the manuscript, acquisition of data, study supervision. Dr. Hunt:
drafting/revising the manuscript, contribution of vital reagents/tools/
patients. Dr. Severt: drafting/revising the manuscript, acquisition of data.
D. Raymond: drafting/revising the manuscript, acquisition of data, study
supervision. Dr. Ozelius: drafting/revising the manuscript, acquisition of
data, study supervision. Dr. Lipton: drafting/revising the manuscript,
analysis or interpretation of data, statistical analysis, study supervision,
obtaining funding. Dr. Bressman: drafting/revising the manuscript, study
concept or design, analysis or interpretation of data, acquisition of data,
study supervision, obtaining funding.
The authors thank Jeannie Soto-Valencia, Monica Sethi, and Paul Soto
(Beth Israel Medical Center) for their assistance in data collection and
recruitment; the subjects, families, and EAS study subjects for their partic-
ipation; and Charlotte Magnotta for recruitment (Einstein Aging Study).
Dr. Saunders-Pullman serves on the Scientific Advisory Board of the
Dystonia Medical Research Foundation. She has received research sup-
port from the NIH/NINDS, the Michael J Fox Foundation for Parkin-
son’s Research, the Thomas Hartman Foundation for Parkinson’s
Research, the Bachmann-Strauss Dystonia Parkinson’s Foundation, and
the Marcled Foundation. She has received an honorarium from GE
Healthcare. K. Stanley reports no disclosures. Dr. Wang receives research
support from Bristol-Myers Squibb. Dr. San Luciano has received re-
search support from the American Academy of Neurology Foundation.
Dr. Shanker serves as a consultant for Teva Pharmaceutical Industries Ltd.
and ECRI. Dr. Hunt reports no disclosures. Dr. Severt has received
speaker honoraria from Teva Pharmaceutical Industries Ltd., Novartis,
Ipsen, and Allergan, Inc.; and receives research support from Teva Phar-
maceutical Industries Ltd., Ceregene, and Chelsea Therapeutics. D. Ray-
mond reports no disclosures. Dr. Ozelius serves on scientific advisory
boards for the Dystonia Medical Research Foundation, the Bachmann-
Strauss Dystonia & Parkinson Foundation, the Benign Essential Blepha-
Neurology 77July 26, 2011
rospasm Research Foundation, and the National Spasmodic Dysphonia
Association; is listed as an author on patents re: Torsin, Torsin genes and
methods of use, and Nucleic acids, methods and kits for the diagnosis of
DYT6 primary torsion dystonia; receives research support from the NIH,
the Dystonia Medical Research Foundation, and the Bachmann Strauss
Dystonia Parkinson Foundation; and receives royalties from Athena Diag-
nostics, Inc. for a patent re: Torsin, Torsin genes and methods of use. Dr.
Lipton serves on scientific advisory boards for Allergan, Inc., Merck Se-
rono,, Neuralieve, Inc., and Pfizer Inc.; has received funding for travel
from the American Headache Society, Cognimed, Diamond Headache
Clinic Research, Market Force Communications, Merck Serono, Mi-
graine Research Foundation, Scienta, and Talley Management; serves as
Associate Editor of Cephalalgia and on the editorial boards of Neurology®
and Headache; receives royalties from publishing Headache in Clinical
Practice (Isis Medical Media, 2002), Headache in Primary Care (Isis Med-
ical Media, 1999), Wolff ’s Headache (Oxford University Press, 2001,
2008), Managing Migraine: A Physician’s Guide (BC Decker, 2008), and
Managing Migraine: A Patient’s Guide (BC Decker, 2008); has received
speaker honoraria from the National Headache Foundation, the Univer-
sity of Oklahoma, the American Academy of Neurology, the Annenberg
Foundation, Merck Serono, GlaxoSmithKline, and Coherex Medical;
serves as a consultant for Allergan, Inc., Autonomic Technologies, MAP
Pharmaceuticals, Inc., Neuralieve, Inc., and Novartis; receives/has re-
ceived research support from AstraZeneca, Ortho McNeil, GlaxoSmithK-
line, Merck Serono, ProEthic Pharmaceutical, Inc., Advanced Bionics, the
NIH/NIA, St. Jude Medical, the Migraine Research Foundation, and the
National Headache Foundation; and holds stock options in Minster Phar-
maceuticals plc. Dr. Bressman serves on scientific advisory boards for the
Bachmann Strauss Dystonia and Parkinson’s Foundation, the Michael J
Fox Foundation for Parkinson’s Research, and the Dystonia Medical Re-
search Foundation; holds a patent re: THAP1 gene testing; and receives
research support from the NIH and the Michael J Fox Foundation for
Received August 7, 2010. Accepted in final form October 25, 2010.
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to sporadic Parkinson’s disease. Neurobiol Aging 2003;
Historical Abstract: July 20, 2010
THE “TORPILLAGE” NEUROLOGISTS OF WORLD WAR I: ELECTRIC THERAPY TO SEND HYSTERICS BACK TO THE
Laurent Tatu, Julien Bogousslavsky, Thierry Moulin, and Jean-Luc Chopard
The French neurologists and psychiatrists who were mobilized during the Great War were confronted with numerous
soldiers with war neuroses, often with novel clinical manifestations such as camptocormia. They addressed hysteria
and pithiatism according to concepts that had been formed before the war, and many doctors considered these soldiers
to be malingerers. As a result, the use of aggressive therapies to enable their prompt return to the battlefront was
advocated. In 1915–1916, Clovis Vincent (1879–1947) developed a method called torpillage, a “persuasive” form of
psychotherapy using faradic and galvanic electric currents, to treat soldiers with “intractable” neuroses. However,
since the treatment was painful, soldiers began to refuse it and, following a publicized trial, the method was
discontinued. Given the influx of soldiers with seemingly incurable neuroses, Gustave Roussy (1874–1948) made an
attempt in 1917 to develop a new method of psychoelectric treatment. In January 1918, he too came up against
soldiers refusing electric treatment. Following a new trial and an unfavorable press campaign, the psycho-faradic
method gradually died out. These extreme medical practices developed to treat psychological trauma during the First
World War subsequently led to the delineation of posttraumatic stress disorder in more recent wars.
Free Access to this article at www.neurology.org/content/75/3/279
Comment from Robert A. Gross, MD, PhD, FAAN, Editor-in-Chief: One of the most-cited Historical Neurology articles, this
paper explored the treatment of psychological symptoms from a more medical perspective.
Neurology 77 July 26, 2011