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JAD-151000

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989
Journal of Alzheimer’s Disease 52 (2016) 989–997
DOI 10.3233/JAD-151000
IOS Press
Severe Brain Metabolic Decreases
Associated with REM Sleep Behavior
Disorder in Dementia with Lewy Bodies
Leonardo Iaccarinoa,1 , Sara Marellib,c,1 , Sandro Iannacconed , Giuseppe Magnanie ,
Luigi Ferini-Strambib,c,∗ and Daniela Perania,c,f,g,h
a Vita-Salute San Raffaele University and Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
b Department
of Clinical Neurosciences, San Raffaele Scientific Institute, Neurology, Sleep Disorders Center,
Milan, Italy
c Vita-Salute San Raffaele University, Faculty of Psychology, Milan, Italy
d Department of Clinical Neurosciences, San Raffaele Scientific Institute, Neurorehabilitation Unit, Milan, Italy
e Department of Neurology, San Raffaele Scientific Institute, Neurology, Milan, Italy
f CERMAC, Vita-Salute San Raffaele University, Milan, Italy
g Istituto di Bioimmagini e Fisiologia Molecolare C.N.R., Segrate, Italy
h Nuclear Medicine Unit, San Raffaele Scientific Institute, Milan, Italy
Handling Associate Editor: Marco Bozzali
Accepted 22 February 2016
Abstract.
Background/Objective: To evaluate the prevalence of REM sleep behavior disorder (RBD) in a sample of Dementia with
Lewy Bodies (DLB) and Alzheimer’s Disease (AD) patients and compare the patterns of brain glucose metabolism in DLB
patients with or without the sleep disturbances.
Methods: In this retrospective study, the presence of probable RBD was ascertained for 27 clinically diagnosed DLB patients
and 11 AD patients by a self-administered RBD Single-Question Screen (RBD1Q), followed by a sleep structured interview
by experts in sleep disorders blinded to clinical information. For 18 F-FDG-PET metabolic comparisons, we considered
an additional 13 DLB patients with negative history for sleep disturbance. We performed DLB within-group comparisons
covarying for age and disease duration.
Results: The RBD1Q questionnaire identified 20 out of 27 DLB RBD+ and 7 out of 27 DLB RBD–. None of the AD
patients was positive to RBD1Q test. 18 F-FDG-PET hypometabolism at the single- and group-level tested by means of an
optimized SPM approach revealed the typical DLB metabolic pattern. Each DLB patient showed a predominant occipital
hypometabolism. The SPM voxel-based comparisons revealed significant brain metabolic differences, namely a more severe
metabolic decrease in DLB RBD+ in the dorsolateral and medial frontal regions, left precuneus, bilateral superior parietal
lobule and rolandic operculum, and amygdala.
Discussion: We found a high prevalence of RBD in DLB and none in AD, as identified by the RBD1Q questionnaire,
indicating its utility in clinical practice. DLB patients with or without RBD show different hypometabolism patterns that
might reflect differences in underlying pathology.
Keywords: Brain metabolism, dementia, dementia with Lewy bodies, 18 F-FDG-PET, REM sleep behavior disorder, sleep
1 These
authors contributed equally to this work.
to: Luigi Ferini-Strambi, MD, PhD, Director, Sleep Disorders Center, University Vita-Salute San Raffaele,
Via Stamira D’Ancona, 20, 20127 Milan, Italy; Full Professor
∗ Correspondence
of Neurology, Sleep Disorders Center, Università Vita-Salute San
Raffaele, Milan, Italy. Tel.: +39 02 2643 3363; Fax: +39 02 2643
3394; E-mail: ferinistrambi.luigi@hsr.it.
ISSN 1387-2877/16/$35.00 © 2016 – IOS Press and the authors. All rights reserved
990
L. Iaccarino et al. / PET in DLB with and without RBD
INTRODUCTION
Dementia with Lewy Bodies (DLB) is the second
most common neurodegenerative dementia with an
incidence of 3.5/100.000 persons each year [1]. It is
characterized by parkinsonian syndrome, cognitive
impairments and sleep disorders, variably associated
at onset, frequently accompanied by hallucinations,
fluctuations in alertness, and autonomic failures [2].
Functional loss is also typical of the syndrome, differentially related to motor and cognitive dysfunctions
[3]. Neuroimaging with Positron Emission Tomography (PET) and Single-Photon Emission Tomography
(SPECT) is considered supportive for diagnosis [2].
18 F-FDG-PET can detect specific patterns of brain
hypometabolism involving particularly the occipital cortex, whereas DAT-SCAN can prove a loss of
Dopaminergic Transporters Activity (DAT) in the
basal ganglia.
REM sleep behavior disorder (RBD) is a parasomnia characterized by a loss of normal muscle
atonia and by complex motor activity during REM
sleep, usually associated with dream mentation [4].
RBD can occur in the absence of any other obvious associated neurologic disorder or in association
with a neurodegenerative disease, in which case it is
considered as symptomatic RBD. RBD is frequently
associated with Parkinson’s disease (PD) [5–7], DLB
[8], and Multiple System Atrophy (MSA) [9, 10]. In
several cases it may even antedate the occurrence of
motor symptoms by decades [11].
Polysomnography (PSG) confirmation of RBD is
essential to make the diagnosis of definite RBD, but
when PSG confirmation of RBD is not feasible in all
cases and by investigators who are not able to perform
sleep studies, it is possible to make the diagnosis of
clinically probable RBD or probable RBD (pRBD)
[12, 13].
Aims of this study were: (i) to evaluate the presence
of pRBD in a sample of DLB patients with an ad hoc
RBD questionnaire (RBD1Q) [14] testing also for its
sensitivity in distinguishing DLB from AD cases in
early phase, and (ii) to assess the patterns of brain glucose hypometabolism using 18 F-FDG-PET in DLB
patients, with and without sleep disturbances.
(mean age ± std: 72.40 ± 7.87) and 11 AD patients
(66.54 ± 8.02) fulfilled the respective criteria for clinical diagnosis [2, 15].
To limit possible artifacts due to different sample sizes in the 18 F-FDG-PET metabolic comparison
between DLB patients with and without RBD, we
considered an additional set of patients (N = 13)
with a clinical diagnosis of DLB [2], and a negative history for sleep disturbances as ascertained
by close relative (when possible with partners). A
total of 20 DLB RBD+ patients were thus compared to 20 DLB RBD– patients (of which 7 RBDwere part of the questionnaire assessment). All the
patients were admitted at the Department of Neurology, San Raffaele Hospital and Vita-Salute San
Raffaele University, Milan, Italy. Informed written
consent was obtained for all the patients. The protocol was approved by the San Raffaele Hospital Local
Ethical Committee. Descriptive statistics and offline
analysis were performed with SPSS software (http://
www.ibm.com/spss, v.20). Demographic summary is
available in Table 1.
REM sleep behavior disorder assessment
The presence of pRBD was ascertained by
a self-administered RBD Single-Question Screen
(RBD1Q) [14], followed by a sleep-structured interview by experts in sleep disorders (LFS, SM), in the
presence of bed partner.
The RBD1Q consists of a single question,
answered “yes” or “no,” as follows: “Have you ever
been told, or suspected yourself, that you seem to ‘act
out your dreams’ while asleep (for example, punching, flailing your arms in the air, making running
movements, etc.)?”. This question has been validated
in several languages (French, German, Japanese, Italian, Spanish, Czech, and Danish) by native-speaking
medical translators or by RBD expert investigators
fluent in English and the local language [14].
Structured interview and RBD1Q data were available for all the patients. Interviewers were blinded
to clinical information at the sleep interview and
RBD1Q administration time.
18 F-FDG-PET
functional imaging
METHODS
Subjects
With regards to the RBD1Q evaluation, we
included 38 patients of which 27 DLB patients
Acquisition
All subjects underwent an 18 F-FDG-PET imaging
scan, using a multi-ring General Electric Discovery STE PET/CT at the Nuclear Medicine Unit, San
Raffaele Hospital, Milan, Italy, following a standard
L. Iaccarino et al. / PET in DLB with and without RBD
991
Table 1
Demographic and CSF measurements summary of the studied cohort
Sample Size
Gender (M/F)
Agea
Years of Education
MMSE
Disease Duration (Cognitive)b,c
Disease Duration (RBD)
Patients w/Visual Hallucinations: n (%)
Patients w/Parkinsonism: n (%)
CSF A␤d,e
CSF T-taud,f
CSF P-taud,g
DLB RBD+
DLB RBD–
AD RBD–
20
16/4
73 ± 6.72
9.25 ± 4.91
17.72 ± 5.66
2.82 ± 1.46
3.78 ± 3.14
10 (50%)
18 (90%)
485.71 ± 208.17
318.71 ± 248.58
64.50 ± 36.36
20
11/9
71.80 ± 9.02
9.88 ± 3.81
20.82 ± 6.07
1.43 ± 1.06
–
7 (35%)
18(90%)
420.70 ± 129.02
279.00 ± 125.61
55.20 ± 25.02
11
5/6
66.54 ± 8.02
8.27 ± 3.95
20.87 ± 4.31
3.43 ± 1.51
–
–
–
318.80 ± 76.01
606.50 ± 314.95
98.20 ± 47.83
Variables are expressed as mean ± std.dev, factors are expressed as frequency (%). a Marks significance in DLB versus AD group comparison
(p = 0.022). b Marks significance in DLB RBD+ versus DLB RBD– group comparison (p = 0.002). c Marks significance in DLB versus AD
group comparison (p = 0.015). d Available for 24/40 DLB and for 10/11 AD. e Marks significance in DLB versus AD group comparison
(p = 0.010). f Marks significance in DLB versus AD group comparison (p = 0.002). g Marks significance in DLB versus AD group comparison
(p = 0.013).
clinical acquisition protocol described elsewhere in
detail [16].
Preprocessing
Image preprocessing was carried out with
SPM5 software (Wellcome Department of Imaging Neuroscience, London, UK; http://www.fil.ion.
ucl.ac.uk/spm) on MATLAB 8 (MathWorksInc, Sherborn, Mass). Images were first spatially normalized
using a custom optimized 18 F-FDG “dementiaspecific” template [17] and then underwent a
Gaussian Kernel smoothing (FWHM: 8 mm) prior
statistical comparisons.
Single-subject and group analysis
Normalized and smoothed 18 F-FDG-PET images
in each patient were voxel-wisely compared to a large
validated normal controls database as previously
reported [16]. Briefly, a two-sample t-test design,
implemented in SPM, was adopted to evaluate wholebrain hypometabolism at individual level, entering
age as a nuisance variable. Cerebral global mean computation (CGM) and proportional scaling (PS) were
used to remove global variation in PET intensities.
Family-Wise Error (FWE) correction for multiple
comparisons at pFWE < 0.05 threshold was adopted,
limiting the minimum significant cluster size to
k = 100. This study design and significance was used
also to verify the DLB pattern of hypometabolism at
the group-level.
Two experts in neuroimaging and two experts in
sleep disorders checked the SPM-t maps at the individual level and the clinical records, respectively.
A cross-check comparison was performed afterwards to identify the DLB cases with SPM typical
hypometabolism pattern positive or negative for
history of sleep disturbances or to the RBD1Q questionnaire.
18 F-FDG-PET
comparison between DLB RBD+
and DLB RBD– groups
We sought to investigate the brain metabolic differences in DLB patients with or without sleep
disturbances by mean of group comparisons.
1. These were first run with a 1st level two-sample
t-test implemented in SPM5 software, comparing directly DLB RBD+ and DLB RBD–
patients 18 F-FDG-PET images and taking into
account age and disease duration (as reported
duration of cognitive deficits prior hospital
admittance, CDO), with CGM computation and
proportional scaling.
2. An additional 2nd level analysis with a twosample t-test was also run, comparing the DLB
RBD+ and DLB RBD– patients individual
contrast images delivered by the SPM singlesubject analysis. Age and disease duration were
taken into account. For both the above analyses,
statistical significance was set to p < 0.025 with
a minimum cluster size of k = 100, not corrected
for multiple comparisons.
3. To further examine the difference between
presence of sleep disturbances and metabolic
changes, we also assessed separately DLB
RBD+ and DLB RBD– group-level hypome-
992
L. Iaccarino et al. / PET in DLB with and without RBD
tabolism in comparison to the normal database,
taking into account age differences, with
CGM computation and proportional scaling.
Statistical significance was set to p < 0.05 FWEcorrected for multiple comparisons with a
minimum cluster size of k = 100.
CSF assessment
Cerebrospinal fluid (CSF) measurements for
amyloid-␤ (A␤), total-tau, and phospho-tau were also
evaluated, considering published pathological cut-off
values to assess biomarker positivity [18], namely (i)
A␤42 <500 ng/L for amyloid, (ii) t-tau >350 ng/L for
total-tau, and (iii) p-tau >61 ng/L for phospho-tau.
RESULTS
Fig. 1. Differences between time from RBD and from cognitive
symptoms onset in DLB RBD+ patients. Barplot showing the differences between the time (years) from cognitive deficits onset and
from sleep disorder onset in the DLB RBD+ patients. Red indicates
RBD duration whereas blue indicates cognitive deficits duration.
REM sleep behavior disorder assessment
The RBD1Q questionnaire identified 20/27 DLB
RBD+ and 7/27 DLB RBD–. None of the AD patients
was positive to the RBD1Q test, therefore leading to
high discrimination abilities of the questionnaire for
diagnosis of pRBD (1.00 specificity, 0.74 sensitivity,
and 0.82 accuracy).
Within-group demographic comparisons
With regards to DLB patients, RBD1Q positivity
was not associated with statistically significant demographic differences except for the CDO, which was
significantly higher in DLB RBD+ patients (MannWhitney non-parametric independent samples test
p = 0.002) (see Table 1 for details). As a further evaluation, we compared in the DLB RBD+ patients the
CDO and the time from onset of sleep disorders
(SDO). The medians of the two distributions were
similar (CDO 3 yrs, SDO 2.87 yrs) and the nonparametric Wilcoxon signed rank test for matched
pairs was not statistically significant (p = 0.507).
More in detail, the slight majority (11/20, 55%) of
the DLB RBD+ patients showed cognitive symptoms
before RBD onset (see Fig. 1).
18 F-FDG-PET
functional imaging
Brain hypometabolism in single-subject and
group analysis
Each DLB patient showed at 18 F-FDG-PET SPM
map brain posterior hypometabolism, involving
temporo-parietal and occipital associative cortices,
reported in literature as the metabolic hallmark
of the disease, supporting diagnosis [2]. In addition, some patients also showed clusters of reduced
metabolism in dorsolateral prefrontal cortex. The
same hypometabolism pattern was confirmed at the
group level (see Fig. 2).
18 F-FDG-PET
comparison between DLB RBD+
and DLB RBD– groups
The first and second level analyses consistently
revealed a more severe metabolic decrease in the DLB
RBD+ with respect to DLB RBD– patients, in the dorsolateral and medial frontal regions, left precuneus,
bilateral superior parietal lobule and rolandic operculum, and amygdala (pUNCORRECTED < 0.025). These
differences were not related to age or disease duration
(see Fig. 3).
In addition, the separate comparisons between
the DLB RBD+ and DLB RBD– group-level
hypometabolism and normal database revealed
a more extensive involvement in posterior brain
regions in the DLB RBD+ group (see Supplementary
Figure 1).
CSF assessment
CSF measurements were available for 34 patients:
14 DLB RBD+, 10 DLB RBD–, and 10 AD.
We found significant differences among A␤, totaltau, and phospho-tau CSF levels in AD compared
to DLB patients (Mann-Whitney non-parametric
independent samples test: p = 0.010, p = 0.002, and
p = 0.013, respectively; see Table 1). In the whole
L. Iaccarino et al. / PET in DLB with and without RBD
993
Fig. 2. 18 F-FDG-PET SPM at the whole group level. Image showing hypometabolism in the whole DLB cohort. SPM thresholded map
(pFWE < 0.05, minimum cluster size k = 100) is (left) overlaid on multiple axial planes of a standard T1 anatomical template and (right)
rendered on a 3D template. Colors index magnitude of hypometabolism. See text for details.
Fig. 3. Brain metabolic decrease in DLB RBD+ versus DLB RBD– groups. Images showing more severe hypometabolism in DLB RBD+
group, revealed by (A) 1st level and (B) 2nd level analyses. Statistical significance was set at p < 0.025 uncorrected, minimum cluster extent
k = 100. Both the comparisons are corrected for age and disease duration. SPM maps are overlaid on multiple axial planes of a standard T1
anatomical template. See text for details.
994
L. Iaccarino et al. / PET in DLB with and without RBD
DLB group, ∼71% of the patients (n = 17/24) were
amyloid positive. Of these 17, 4 patients were also
positive for pathological total-tau and phospho-tau
levels. As for comparisons between DLB RBD+
and DLB RBD– patients, there were no significant
differences (A␤ p = 0.437, total-tau p = 0.709, and
phospho-tau p = 0.796, Mann-Whitney U test). Eight
DLB RBD– patients (80%) were amyloid positive,
and three of them were also positive for total-Tau
and phophos-Tau. Within the DLB RBD+ group, 64%
(n = 9/14) of the patients were amyloid positive and
only one patient was also positive for total-Tau and
phospho-Tau.
DISCUSSION
This 18 F-FDG-PET imaging study in DLB, using
a voxel-based SPM approach at single-subject level,
showed the specific and typical DLB brain metabolic
pattern in each individual DLB patient. A number
of studies in literature have reported brain glucose
hypometabolism in DLB, highlighting the specific
occipital pattern that is considered supportive for
clinical diagnosis in the currently adopted criteria
[2]. In the present study, by using an optimized
18 F-FDG-PET SPM analysis, we confirmed the pattern of predominant occipital hypometabolism in
each DLB case, which extended to parietal, temporal
and dorsolateral prefrontal cortex, possibly following
long-distance occipito-frontal deafferentations and
alpha-synuclein spreading.
With regards to the evaluation of RBD1Q and the
comparisons between the AD and DLB dementia
groups, 74% of the evaluated DLB patients but none
of the AD patients were affected by pRBD. This is
coherent with the rarity of RBD in AD-pathology
and its frequent occurrence in synucleinopathy conditions [19], witnessed by its inclusion among the
current DLB diagnostic criteria [2]. It has been suggested that RBD1Q could be used for the assessment
of RBD prevalence in broad-scale epidemiologic surveys of disease [19]. Our study seems to indicate that
RBD1Q may also be useful in the clinical practice
in the evaluation of demented subjects. It is of note
that some patients (n = 5) had a very long history of
RBD symptoms (up to 10 years) with only a more
recent manifestation of cognitive impairments (2–3
years history) (see Fig. 1). Therefore, these subjects
first had an idiopathic RBD (iRBD) presentation and
then after several years developed cognitive deficits,
progressing to a DLB diagnosis. A recent obser-
vational cohort study with postmortem assessment
reported in 44 iRBD patients the development of
DLB (n = 14), PD (n = 16), MSA (n = 1), mild cognitive impairment (MCI) (n = 5) within a median of
12 years (range 3–23) between estimated RBD onset
and final diagnosis [20]. This predementia phase in
alpha-synuclein pathology is characterized by iRBD
that has been shown to begin even 50 years before the
appearance of the other motor and/or cognitive symptoms [21]. Notably, in our sample, the majority of the
DLB RBD+ patients (11/20, 55%) showed cognitive
symptoms before RBD onset. It is known that DLB
patients might show no RBD before development of
dementia [22]. Moreover, a diagnostic delay of RBD
(8.7 ± 11 years) has been reported in relation to mild
or infrequent occurrence of sleep behavior [23]. DLB
RBD+ patients presented a CDO (reported duration
of cognitive deficits prior hospital admittance) significantly longer than DLB RBD- patients, despite
a comparable Mini-Mental State Examination score
(see Table 1). This result seems to suggest that, for
DLB RBD- patients, it takes a shorter time to reach a
significant degree of cognitive decline, while it takes
longer for DLB patients with RBD. This is consistent with the hypothesis by [24], suggesting that
these two clinical phenotypes might reflect two different underlying pathologies. In particular, DLB RBDpatients are more likely to bear a mixed AD-DLB
pathology, thus possibly leading to a faster cognitive
decline.
To the best of our knowledge, there is no evidence in literature on metabolic differences in DLB
patients with and without sleep disturbances. Here,
we showed that significant differences in the amount
of brain glucose metabolism may occur. The DLB
RBD+ with respect to DLB RBD– patients showed
a more severe metabolic decrease in the posterior
typically affected cerebral regions and particularly
in the bilateral superior parietal lobule and rolandic
operculum, and in the left precuneus, and in addition in the dorsolateral and medial frontal regions and
amygdala. These results survived the statistical corrections for age and disease duration. The amygdala is
known for its involvement in synucleinopathies [25,
26]. A previous study found a significant negative
association between Lewy bodies burden and amygdala volume [27], while this relationship was only
trending toward significance in another study [28].
The present findings consistently show a more severe
hypometabolism in DLB RBD positive patients, who
are expected to carry a more “pure” synuclein pathology [24].
L. Iaccarino et al. / PET in DLB with and without RBD
With regards to the metabolic involvement of posterior parietal and frontal regions, given their role in
dorsal and ventral visual streams and their relation
with presence of visual hallucinations in DLB [29,
30], we also assessed whether visual hallucinations
were differentially present within the DLB RBD+
and DLB RBD– groups. The DLB RBD+ patients
had a slightly higher frequency of concomitant visual
hallucinations (50%, 10/20) with respect to the DLB
RBD– group (35%, 7/20). This difference, however,
was not significant (Fisher’s Exact test, p = 0.523).
Therefore, in the present findings, visual hallucinations represent a limited factor. Further studies on a
larger dataset will be necessary to shed more light on
this crucial aspect. The brain metabolic differences
we found between DLB RBD+ and RBD– groups
might also reflect different patterns of both underlying pathologies and of the associated neurotransmission alterations. Consistently, in a previous study,
Kotagal and co-workers reported PD RBD+ patients
with a more severe neocortical, limbic, and thalamic
cholinergic denervation with respect to the PD RBD–
as measured in vivo with 11 C-DTBZ [31]. The authors
concluded that the presence of RBD symptoms might
index a degeneration of the cholinergic system [31].
Given the common neuropathology (alpha-synuclein
accumulation) in DLB and PD [32, 33], we speculate
that the present 18 F-FDG-PET findings might indicate a more severe alteration of the cholinergic system
in DLB with RBD. Previous studies investigated the
differences in white- and gray-matter abnormalities
between early PD patients with or without RBD [34,
35]. With regards to brain atrophy, there were some
structural differences, namely greater degeneration
in early PD with RBD in several cerebral regions.
A postmortem study in AD and DLB cases showed
that in autopsy-confirmed cases with and without
RBD, there were variable atrophy patterns [28]. The
RBD negative cases presented more severe atrophy
in AD-signature regions, and a higher Braak neurofibrillary tangle stage. The pathologic probability
of clinical DLB was, however, higher in the RBD
positive group, as well as the higher frequency of
parkinsonism and visual hallucinations. Therefore,
different studied cohorts reported variable findings
at difference to the present study where all the RBD
positive and negative patients had a clinical diagnosis of probable DLB and comparable frequency of
parkinsonism and visual hallucinations (see Table 1).
The present findings show higher CSF amyloid in
DLB RBD+ patients when compared to DLB RBD–
patients, even if this difference was not statistically
995
significant (p = 0.437 Mann-Whitney U test). These
findings may still indicate that DLB RBD+ patients
may present with a more “pure” synuclein-driven
pathology, with respect to a greater concomitant
Alzheimer pathology in DLB RBD– patients [24]. On
the basis of the neuropathological differences found
between DLB RBD+ and DLB RBD– patients, some
authors have suggested different DLB subtypes [24].
Future neuroimaging studies in DLB larger samples,
with or without RBD, measuring either amyloid- or
tau-burden and neurodegeneration (18 F-FDG-PET)
might be of utmost interest for the identification of
possible DLB subtypes.
A limitation of our study is the lack of PSG evaluation. However, other recent studies enrolled patients
with the diagnosis of “pRBD” in absence of PSG
study [28, 34, 36, 37].
Some studies reported that clinical characteristics differ between PD with and without RBD [38,
39]. Our study also shows that 18 F-FDG-PET findings differ between DLB with and without RBD. As
recently suggested for PD patients [40], the identification of different subtypes of neurodegenerative
disorders also in relation to the presence of RBD,
could be of fundamental importance for potential
neuroprotective intervention with disease-modifying
therapy.
DISCLOSURE STATEMENT
Authors’ disclosures available online (http://jalz.com/manuscript-disclosures/15-1000r1).
SUPPLEMENTARY MATERIAL
The supplementary material is available in the
electronic version of this article: http://dx.doi.org/
10.3233/JAD-151000.
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