Genotype and Phenotype in Parkinson's Disease: Lessons in Heterogeneity From Deep Brain Stimulation

Abstract

Variation in the genetic risk(s) of developing Parkinson's disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l-dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype-phenotype relationships.

Full text

Genotype and Phenotype in Parkinson’s Disease:
Lessons in Heterogeneity From Deep Brain Stimulation
Aikaterina Angeli, MD,
1
Niccolo E. Mencacci, MD,
2,3
Raquel Duran, MD,
2
Iciar Aviles-Olmos, MD,
1
Zinovia Kefalopoulou, MD, PhD,
1
Joseph Candelario, BSc,
1
Sarah Rusbridge, BSc,
4
Jennifer Foley, PhD,
4
Priyanka Pradhan, PhD,
4
Marjan Jahanshahi, PhD,
1
Ludvic Zrinzo, MD, PhD,
1
Marwan Hariz, MD, PhD,
1
Nicholas W. Wood, PhD,
FRCP,
2
John Hardy, PhD, FRS, FMedSci,
2
Patricia Limousin, MD, PhD,
1
and Tom Foltynie, MRCP, MD
1
*
1
Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, Queen Square, London, United Kingdom
2
Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom
3
Department of Neurology and Laboratory of Neuroscience, “Dino Ferrari” Centre, Universit

a degli Studi di Milano-IRCCS Istituto
Auxologico Italiano, Milan, Italy
4
Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom
ABSTRACT: Variation in the genetic risk(s) of devel-
oping Parkinson’s disease (PD) undoubtedly contributes to
the subsequent phenotypic heterogeneity. Although patients
with PD who undergo deep brain stimulation (DBS) are a
skewed population, they representavaluableresourcefor
exploring the relationships between heterogeneous pheno-
types and PD genetics. In this series, 94 patients who
underwent DBS were screened for mutations in the most
common genes associated with PD. The consequent
genetic subgroups of patients were compared with respect
to phenotype, levodopa (
L-dopa), and DBS responsiveness.
An unprecedented number (29%) of patients tested positive
for at least 1 of the currently known PD genes. Patients with
Parkin mutations presented at the youngest age but had
many years of disease before needing DBS, whereas gluco-
cerebrosidase (GBA) mutation carriers reached the thresh-
old of needing DBS earlier, and developed earlier cognitive
impairment after DBS. DBS cohorts include large numbers
of gene positive PD patients and can be clinically instructive
in the exploration of genotype-phenotype relationships.
Key Words: genetics; Parkinson’s disease; pheno-
type; deep brain stimulation; heterogeneity
Patients with Parkinson’s disease (PD) show marked
heterogeneity in their clinical features in relation to
motor phenotype, rate of progression, and development
of cognitive impairment.
1
Clinical studies of heterogene-
ity have been complemented by studies of the relation
between PD pathophysiological mechanisms and PD risk
factors.
2–4
Some aspects of PD heterogeneity almost cer-
tainly relate to the recognized genes
5,6
with superimposed
environmental, epistatic, as well as stochastic modifiers of
PD phenotype. Several studies have described the pheno-
type of patients with specific genetic mutations
7–9
;how-
ever, direct comparisons of PD phenotype between
different genetically defined groups are scarce.
10
Patients with PD who undergo deep brain stimulation
(DBS) tend to have a young age at onset and, thus, prob-
ably include an over-representation of genetic forms of
PD. In this study, an extensive genotyping of a series of
patients with PD who underwent DBS surgery was per-
formed, and subsequent comparisons were made of clini-
cal phenotypes among genetic subgroups both on and off
dopaminergic medication along with responses to DBS.
Patients and Methods
Clinical Assessments
All patients were followed at the National Hospital
for Neurology and Neurosurgery, Queen Square and
------------------------------------------------------------
*Correspondence to: Dr. Thomas Foltynie, Box 146, National Hospital
for Neurology & Neurosurgery, Queen Square, London, WC1N 3BG
United Kingdom; t.foltynie@ucl.ac.uk
Funding agencies: This work was supported by Parkinson’s UK (grant
number K-0901 awarded to T.F.), the National Institute for Health
Research (NIHR) UCL/UCLH Biomedical Research Centres funding
Scheme and The Wellcome Trust/Medical Research Council (MRC)
funded UK Parkinson’s disease consortium.
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: 1 February 2013; Revised: 12 March 2013; Accepted: 17
April 2013
DOI: 10.1002/mds.25535
V
C
2013 The Authors. Movement Disorders published by Wiley on b-
ehalf of The Movement Disorder Society.
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.
RESEARCH ARTICLE
Movement Disorders, Vol. 00, No. 00, 2013 1

underwent DBS between 2002 and 2011. Basic demo-
graphic details were recorded. The levodopa (
L-dopa)
equivalent dose was derived using standard
formulae.
11
The selection of surgical candidates and targets was
performed after assessments, including
L-dopa chal-
lenge, using the Unified Parkinson’s Disease Rating
Scale (UPDRS) part 3 (motor examination) in the
practically defined “OFF-state” and “ON-state” and
also using UPDRS parts 1 (nonmotor activities of daily
living), 2 (motor activities of daily life), and 4 (motor
complications). Additional assessments included brain
magnetic resonance imaging and neuropsychological
assessments (including the Mattis Dementia Rating
Scale [DRS-2]).
UPDRS part 3 subscale scores were derived to quan-
tify tremor (items 20 and 21), akinesia and rigidity
(items 22–26 and 31), and axial features (items 18,
19, and 27–30). Part 4 of the UPDRS was divided into
items 32 through 34 for dyskinesia and items 35
through 39 to reflect OFF periods.
The optimal DBS target was chosen according to the
frequency and severity of OFF-symptoms, dyskinesia,
tremor, speech-intelligibility, and cognition. DBS was
performed using a standard technique that has been
described previously.
12–15
Genotyping consent was
obtained from all patients.
Postoperative assessments were performed 12
months after DBS surgery. Patients who refused to
have the stimulation switched off had their preopera-
tive “OFF-medication” scores imputed. A subset of 37
patients with >5 years of follow-up post-DBS under-
went repeat cognitive assessment and had the mean
annual change on the DRS-2 between baseline and
follow-up calculated.
Genotyping
Genetic testing for PD genes was performed in
accordance with the service supplied by the Depart-
ment of Neurogenetics, Queen Square. Multiplex
ligation-dependent probe amplification (MLPA) was
performed according to manufacturer’s instructions
using the P051 Salsa MLPA Parkinson probe set
(MRC Holland, Amsterdam, the Netherlands). This
set includes probes that detect exonic rearrangements
in PARK1 (synuclein alpha [SNCA]; exons 1–6),
PARK2 (Parkin: exons 1–12), PARK6 (phosphatase
and tensin homolog-induced putative kinase 1
[PINK1]; exons 1–8), PARK7 (DJ1; coding exons 3, 5,
6, and 7), PARK8 (leucine-rich repeat kinase 2
[LRRK2]; exons 1, 2, 10, 15, 27, 41, and 49), the
Ala30Pro mutation in PARK 1 (SNCA), and the
Gly2019Ser mutation in PARK8 (LRRK2). Patients
who were identified as positive for G2019S point
mutations had their results confirmed by Sanger
sequencing.
In addition, the Parkin (12 exons) and glucocerebro-
sidase (GBA) (11 exons) coding region and the flank-
ing intronic sequences were completely screened by
Sanger sequencing. The primers and polymerase chain
reaction (PCR) conditions we used are available on
request. PCR products were bidirectional sequenced
using the BigDye Terminator version 3.1 sequencing
chemistry, then loaded on the ABI3730xl genetic ana-
lyzer (Applied Biosystems, Foster City, CA).
Statistical Analysis
All statistical tests were performed using the Stata
statistical software package (version 8; StataCorp LC,
College Station, TX). The v
2
test was used for cate-
gorical data. Continuous data were checked for nor-
mality, and 1-way analysis of variance was used to
compare subgroups. Post hoc comparisons were per-
formed using Sidak’s method. Kruskal Wallis and non-
parametric post hoc comparisons also were used as
appropriate.
Results
Data are reported for 94 unselected patients with
PD who underwent DBS. The mean (6 standard devi-
ation [SD]) age of patients at the onset of symptoms
was 40.4 6 8.2 years (range, 7–58 years). Of these 94
patients, 27 (29%) had at least 1 mutation in a PD
gene. The results of genotyping for this cohort are pre-
sented in Table 1.
Genotypes
Parkin
All single mutation carriers are reported, but we
have only included Parkin homozygotes/compound
heterozygotes for phenotypic comparisons. Eight indi-
viduals had Parkin mutations, of which 5 patients had
2 mutations, and 3 patients had a single mutation (1
of whom also had a GBA T369M mutation).
GBA
Sixteen patients had at least 1 mutation in the GBA
gene, most common of which were the E326K
mutation.
9,16
LRRK2-G2019S
Five patients were identified with the G2019S muta-
tion. One patient with a G2019S mutation also car-
ried the E326K GBA mutation. The remaining 67
patients had no mutation detected.
Phenotypes
The mean age at onset for the individuals who had
2 Parkin mutations (24.0 years) was younger than the
age of those who had GBA mutations (P 5 0.0009)
PD HETEROGENEITY, GENOTYPES, AND DBS
2 Movement Disorders, Vol. 00, No. 00, 2013

and those without mutations (P 5 0.006) (Table
1).The mean duration of PD (6 SD) in patients at
DBS surgery was 15.0 6 6.6 years (range, 3.8–38.0
years). Patients with Parkin mutations had a longer
duration of disease at surgery than all other sub-
groups, whereas patients with GBA mutations had a
shorter duration of disease at surgery compared with
the Parkin mutation and mutation-negative subgroups
(P 5 0.001) (Table 2).
L-Dopa challenge revealed a
mean UPDRS part 3 improvement of 68% in the
group as a whole. UPDRS part 4 dyskinesia scores
were higher in the patients with Parkin mutations
TABLE 1. Description of abnormal genetic findings in a cohort of 94 patients with PD who underwent deep brain stimulation
surgery
Genetic test results
No. of
patients (sex) Description
Mean age 6 SD/age
at symptom onset, y Family history
a
Parkin double
mutation carriers
24 6 11.1
4 (3 M, 1 F) Homozygous [c.101_102delAG] 30 Nil
c.1289G>A, p.G430D and
c.823C>T; p.Arg275Trp
20 Sibling
c.337_376del and c.465–466del 36 Nil
Homozygous deletion of exon 3 and
4
27 Sibling
c.823C>T; p.Arg275Trp and Hetero-
zygous duplication of exon 6
7 Unknown
Parkin single
mutation carriers
5 (4M, 1F) c.1000C>T; p.Arg334Cys 41 Nil
c.337_376del, p.P113TfsX51 39 Nil
c.1310C>T; p.P437L and GBA
T369M
b
39 Nil
GBA confirmed
mutation
42.9 6 6.2
16 (9 M, 7 F) R463C/R463C 45 Parent
L444P/E326K 34 Nil
N370S 45 2 Second-degree
relatives
D409H 39 Nil
recNcil 40 Nil
R463C 45 Parent
N188S 49 Nil
R275Q 42 Parent
IVS2 1 1G>A 41 Nil
L444P 45 Nil
E326K/E326K 42 1 Third-degree relative
E326K 36 1 Second-degree relative
E326K 51 Parent
E326K 58 Nil
E326K and LRRK2 G2019S
b
35 Nil
T369M and parkin c.1310C>T;
p.P437L
b
39 Nil
LRRK2 43 6 8.7
5 (3 M, 2 F) G2019S 40 Nil
G2019S 36 Parent
G2019S 49 Nil
G2019S 55 Parent
G2019S and GBA-E326K
b
35 Nil
No mutation found
67 (46 M, 21 F) 40.8 6 7.2 Parent, n 5 9
Sibling, n 5 2
Grandparent, n 5 2
Half sibling, n 5 1
Cousin, n 5 4
Aunt, n 5 2
a
Family history data details the number of patients reporting a positive family history of PD, together with affected relative in each genetic subgroup.
b
Note that
the numbers add up to 96, because 2 individuals who carried 2 confirmed PD mutations are represented twice in the table.SD, standard deviation; M, males;
F, females; GBA, glucosidase beta acid; LRRK2, leucine-rich repeat kinase 2.
ANGELI ET AL.
Movement Disorders, Vol. 00, No. 00, 2013 3

despite their receipt of lower doses of L-dopa. No
other motor phenotypic differences were detectable
(Table 3).
There was a difference in the target choice for DBS
according to genotypic subgroups (v
2
statistic, 29.1;
P < 0.001), with an excess of patients who had Par-
kin and GBA mutations allocated to bilateral globus
pallidus internus DBS (GPi-DBS) rather than subtha-
lamic nucleus DBS (STN-DBS). The percentage
improvement in the UPDRS part 3 score “OFF-
medication” was less with bilateral GPi-DBS than
with STN-DBS for all groups (P 5 0.001) (Table 4).
Two mutation-negative patients underwent bilateral
GPi-DBS and had worse OFF-medication/ON-stimu-
lation scores compared with their preoperative OFF-
medication assessment, but both experienced
improvement in dyskinesias.
There was no significant difference in the degree of
improvement achievable with STN-DBS between
mutation-negative patients and patients who had Par-
kin, GBA, or LRRK2 mutations. There was a worsen-
ing of postoperative OFF-medication/OFF-stimulation
scores compared with preoperative OFF-medication
scores in patients who underwent STN-DBS. Note
that medication doses are substantially reduced post-
operatively; therefore, the practically defined “OFF”
may be closer to the true “OFF” at this time point.
Longitudinal 5-year follow-up data with respect to
cognition were available for 35 individuals; all had
undergone STN-DBS, and 6 had GBA mutations. The
mean 6 SD decline in Mattis DRS-2 scores for patients
with GBA mutations was 4.4 6 7.3 points per year
compared with 0.5 6 0.9 points per year among
mutation-negative patients.
TABLE 2. Preoperative Unified Parkinson’s Disease Rating Scale scores and response to L-dopa according to genetic
subgroup
Mean 6 SD
UPDRS-II UPDRS-III UPDRS-IV
Genetic test results
Duration of
PD at DBS
assessment, y
LED, mg UPDRS-I Off meds On meds Off meds On meds
Percentage
improvement
in score
with
L-dopa
Dyskinesia
score
Off
meds
score
Parkin (compound
heterozygotes/
homozygotes;
N 5 5)
25.2 6 12.8 960 6 611 1.7 6 2.1 24.3 6 4.0 6 6 6.2 57.0 6 11.2 21.0 6 6.4 61.0 6 18.3 5.3 6 3.9 3.5 6 1.3
GBA (confirmed
mutation;
N 5 16)
11.2 6 5.0 1143 6 540 1.5 6 1.5 23.1 6 12.3 10.9 6 11.8 51.3 6 14.0 18.0 6 15.4 66.9 6 18.6 3.0 6 2.7 4.6 6 2.1
LRRK2 (N 5 5) 12.1 6 1.8 1317 6 803 1.2 6 1.1 26.8 6 7.9 4.5 6 4.4 65.4 6 14.9 10.8 6 5.1 84.9 6 5.5 4.2 6 3.1 5.2 6 1.3
No mutation
found
(N 5 67)
15.1 6 5.5 1259 6 559 2.0 6 1.6 22.9 6 7.9 8.0 6 7.2 47.4 6 14.7 15.6 6 11.3 68.5 6 19.3 3.0 6 2.2 4.5 6 1.3
SD, standard deviation; UPDRS-I through UPDRS-IV, Unified Parkinson’s Disease Rating Scale parts 1 (nonmotor activities of daily living), 2 (motor activities of
daily living), 3 (motor examination), and 4 (motor complications), respectively; DBS, deep brain stimulation; meds, medication; LED,
L-dopa equivalent dose;
GBA, glucosidase beta acid; LRRK2, leucine-rich repeat kinase 2.
TABLE 3. Preoperative Unified Parkinson’s Disease Rating Scale motor scores “off” and “on” L-dopa according to genetic
subgroup
a
UPDRS score: Mean 6 SD
Off
L-dopa On L-dopa
Genetic test results Tremor Bradykinesia/rigidity Axial Tremor Bradykinesia/rigidity Axial
Parkin (compound heterozygotes/
homozygotes; N 5 5)
6.4 6 3.8 36.4 6 7.4 14.2 6 4.2 1.4 6 1.7 13.0 6 4.5 6.6 6 2.4
GBA (confirmed mutation; N 5 16) 6.9 6 5.1 31.2 6 11.0 13.1 6 5.7 1.2 6 1.9 12.1 6 11.0 4.7 6 4.6
LRRK2 (N 5 5) 9.4 6 2.2 40.8 6 8.8 15.2 6 6.7 0 6 0.0 8.3 6 3.6 2.5 6 2.1
No mutation found (N 5 67) 7.3 6 5.3 29.4 6 10.3 10.8 6 4.8 1.7 6 3.4 10.3 6 7.4 3.6 6 2.9
a
There were no significant differences in the motor phenotype according to genetic subgroup. Tremor was seen in all subgroups, and the proportion of tremor
compared with akinesia/rigidity or axial features was similar in each group.UPDRS, Unified Parkinson’s Disease Rating Scale; SD, standard deviation; GBA,
glucosidase beta acid; LRRK2, leucine-rich repeat kinase 2.
PD HETEROGENEITY, GENOTYPES, AND DBS
4 Movement Disorders, Vol. 00, No. 00, 2013

Discussion
The results from this study confirm that patients
who undergo DBS surgery are a valuable resource for
identifying genetic forms of PD. The frequency of
mutation-positive patients with PD was much greater
in our cohort (27 of 94 patients; 29%) than in
population-representative cohorts of PD.
17
Although
the use of DBS cohorts facilitates the rapid identifica-
tion of mutation-positive patients for study, patients
who have major cognitive or psychiatric problems or
a relative lack of
L-dopa response are excluded; there-
fore, the relevance of such data to the broader popula-
tion of PD patients is partially limited. Patients in our
cohort underwent detailed screening for the most com-
mon PD genes; nevertheless, not every gene previously
linked to PD was sequenced. Therefore, some patients
with genetic forms of PD may have been misclassified
as mutation-negative.
Apart from confirming that patients with Parkin
mutations had more severe
L-dopa–induced dyskinesia,
no consistent phenotypic difference was identified
between mutation-positive and mutation-negative sub-
types at a single time point. This said, the small num-
bers of patients in each genetic subgroup, together with
variable disease duration between groups, limits the
power of this study to reach definite conclusions. In a
previous study that examined the phenotype of GBA
patients, bradykinesia as a presenting feature was the
only difference compared with GBA-negative patients.
9
Together with our data, this suggests that the currently
known genetic mutations all lead to a similar pattern/
variety of patterns of neurodegeneration.
However, longitudinal data are more revealing. Dis-
ease duration at DBS differs significantly between
genetic subgroups. Patients with Parkin mutations are
younger at the onset of disease and have earlier dyski-
nesia, but they have longer disease duration before
DBS, indicating a more indolent form of the disease.
The patients in our study who had Parkin mutations
were receiving lower doses of
L-dopa replacement than
all other groups, probably because of their increased
severity of dyskinesia. PD patients with GBA mutations
required DBS earlier in their disease course, because
they developed disabling motor symptoms at an earlier
stage despite conventional oral treatment, consistent
with other published studies suggesting that patients
with PD who have GBA mutations also have higher
rates of cognitive decline (irrespective of DBS).
18
Previous reports have documented the generally
good response to DBS of small numbers of patients
with Parkin,
19,20
Pink-1,
19,20
and LRRK-2 muta-
tions.
19,21,22
However, the long-term response of
patients with GBA mutations to DBS is less well
known. In the current series, the response to either
STN-DBS or GPi-DBS did not differ significantly
between the subgroup with GBA mutations (at 1 year)
and any other subgroup. However, our longitudinal
TABLE 4. Target selection and response to deep brain stimulation according to target and genetic subgroup
UPDRS-III score: Mean 6 SD UPDRS-IV
Post-op
Dyskinesia score:
Mean 6 SD
Genetic
test results
No. of
patients
DBS
target
Disease
duration at DBS:
Mean 6 SD, y
Pre-op:
Off meds
Off meds/
off stim
Off meds/
on stim
Percentage
improvement
in UPDRS-III
score off meds/
on stim vs
pre-op off
meds
Post-op:
On meds/
on stim
Mean 6 SD
reduction in
LED, mg Pre-op Post-op
Percentage
improvement
in post-op
vs pre-op
UPDRS-IV
score
Parkin
(compound
Hets/Homozy’s)
3 GPi 21.1 6 16.2 53.3 6 13.9 43.3 6 16.4 42.0 6 19.0 21% 27.3 6 17.6 2237 6 315 8.0 6 1.4 1.67 6 2.0 70%
2 STN 31.3 6 0.6 62.5 6 3.5 84.0 6 22.6 43.0 6 0.0 31% 23.5 6 6.4 20 6 594 2.5 6 3.5 2.0 6 1.4 20%
GBA
(confirmed
PD mutation)
2 GPi 15.5 6 5.3 64.5 6 21.9 66.5 6 19.1 50.0 6 19.8 22% 41.0 6 15.6 1005 6 77 8.5 6 0.7 0.5 6 0.7 94%
13 STN 10.9 6 4.9 50.5 6 12.4 56.1 6 18.8 28 6 11.4 40% 15.9 6 10.4 146 6 510 2.4 6 1.7 1.5 6 1.6 37%
1 VIM
(unilateral)
3.9 35 35 20 43% 8 445 0 0 —
LRRK2 5 STN 12.1 6 1.8 65.4 6 14.9 69.2 6 12.4 30.6 6 16.1 53% 14.0 6 8.1 586 6 495 4.2 6 3.1 1.4 6 2.6 50%
No mutation
found
2 GPi 21.7 6 0.5 40.5
6 13.4 78 6 7.1 51.0 6 7.1 228% 25.5 6 4.9 227 6 89 6.0 6 1.4 3.5 6 0.7 42%
65 STN 14.8 6 5.4 47.6 6 14.8 50.0 6 15.4 24.6 6 11.3 48% 15.0 6 9.0 468 6 494 3.1 6 2.2 3.0 6 2.2 26%
SD, standard deviation; UPDRS-III, Unified Parkinson’s Disease Rating Scale, part 3 (motor examination); meds, medication; stim, stimulation; LED, L-dopa
equivalent dose; UPDRS-IV, Unified Parkinson’s Disease Rating Scale, part 4 (motor complications); DBS, deep brain stimulation; GPi, globus pallidus internus;
STN, subthalamic nucleus; GBA, glucosidase beta acid; VIM, ventral intermediate nucleus; LRRK2, leucine-rich repeat kinase 2.
ANGELI ET AL.
Movement Disorders, Vol. 00, No. 00, 2013 5

follow-up of the subgroup with GBA mutations sug-
gested a faster rate of cognitive decline after DBS. A
previous report of 3 patients with GBA mutations
who underwent STN-DBS also identified a more
aggressive process that led to both cognitive impair-
ment and axial impairments
23
; whereas, of 2 other
patients with GBA mutations who underwent STN-
DBS, 1 had early cognitive decline, and the second
had persistent benefit.
9
Whether there is an interaction
between GBA status and the risk of subsequent cogni-
tive decline after STN-DBS needs to be clarified.
More aggressive disease in patients who have GBA
mutations may have relevance from a therapeutic
standpoint in terms of supporting the earlier introduc-
tion of
L-dopa and possibly the use of bilateral GPi-
DBS rather than bilateral STN-DBS (because there are
likely to be additional negative cognitive consequences
of STN-DBS
24
). Further prospective data would be
needed to confirm this. Our data support the idea that
the heterogeneity of PD should be considered longitu-
dinally in terms of the rate of progression of motor
and nonmotor features rather than the detailed scru-
tiny of purely cross-sectional data.
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6 Movement Disorders, Vol. 00, No. 00, 2013