At room temperature in water: efficient hydrogenation of furfural to furfuryl alcohol with a Pt/SiC-C catalyst

Article abstract of DOI:10.1039/c8ra08429g

Selective hydrogenation of furfural (FAL) to furfuryl alcohol (FOL) is challenging because of many side reactions. The highly selective hydrogenation of FAL to FOL can be achieved over a Pt catalyst supported on nanoporous SiC-C composites even at room temperature in water. A Pt/SiC-C-200-H₂ catalyst, which had a Pt loading of 3 wt% and was reduced in flowing hydrogen at 500 °C after calcination in air at 200 °C for 2 h, furnished complete FAL conversion and over 99% selectivity to FOL at 25 °C under 1 MPa of hydrogen in water. The kinetic behaviour of the selective hydrogenation of FAL to FOL with the 3 wt% Pt/SiC-C-200-H₂ catalyst was also investigated and the turnover frequency (TOF) reached 1148 h^?1. Moreover, the Pt/SiC-C catalyst is more active than other Pt catalysts supported on ordered mesoporous carbon CMK-3, activated carbon, periodic mesoporous silica SBA-15 or Al₂O₃. Detailed characterization using XRD, N₂-sorption, SEM, TEM and XPS techniques reveals that the striking performance of the Pt/SiC-C catalyst can be attributed to the optimal metal-support interaction and the interfacial effect.

Full text of DOI:10.1039/c8ra08429g

Neuropsychologia xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Neuropsychologia
journal homepage: www.elsevier.com/locate/neuropsychologia
Similarities and differences in cerebellar grey matter volume and disrupted
functional connectivity in idiopathic Parkinson's disease and multiple
system atrophy
a,1
b,1
c
c
d
c,⁎
Na Wang , Liang Zhang , HuaGuang Yang , Hu Liu , XiaoGuang Luo , GuoGuang Fan
b
c
d
a
Huashan Hospital Fudan University, Department of Radiology, China
Fudan University Shanghai Cancer Center, Department of Interventional Radiology, Shanghai, China
The First Affiliated Hospital of China Medical University, Department of Radiology, China
The First Affiliated Hospital of China Medical University, Department of Neurology, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Objective: This study investigated the potential differences in changes to cerebellar grey matter volume (GMV)
and functional connectivity (FC) and the association between them, which might elucidate cerebellar function in
multiple system atrophy (MSA) and idiopathic Parkinson's disease (IPD).
Cerebellum
Grey matter volume
Dentate nucleus
Functional connectivity
Methods: Resting-state functional magnetic resonance imaging and three-dimensional T1 scans were obtained
from 38 IPD, 62 MSA, and 59 healthy controls (HC). Seed-based connectivity analysis and voxel-based mor-
phometry analysis were performed to assess the changes of cerebellar FC and GMV between the patient groups.
Result: Decreased cerebellar GMV was found in the motor cerebellum in both patient groups relative to HC, and
broader reduction of GMV was observed in both cognitive and motor cerebellum in MSA compared with IPD and
HC. Compared with IPD, the MSA group exhibited decreased FC between bilateral dentate nucleus (DN) and
default mode network (DMN). Decreased intracerebellar FC was observed in both patient groups relative to HC.
Cerebellar GMV was positively correlated with FC of intracerebellum and DN-DMN in MSA. Motor/cognitive
scores were associated with DN-DMN FC, with considerable cerebellar GMV loss in MSA patients.
Conclusion: Cerebellar GMV loss and cerebellar FC alterations showed similarities in IPD and MSA, along with
more widespread changes to GMV in motor and cognitive cerebellum and altered DN-DMN FC in MSA. Further
research is needed to better describe the alterations of cerebellar GMV in the cognitive cerebellum and asso-
ciation between cerebellar GMV and intracerebellar FC during the early stages of MSA and IPD.
1
. Introduction
Idiopathic Parkinson's disease (IPD) and multiple system atrophy
motor, higher-order cognitive, and emotional processing, the cere-
bellum has gained considerable attention in studies of IPD and MSA
patient groups (Leggio and Molinari, 2015; Liu et al., 2013; Stankovic
et al., 2014). However, similarities and differences between cerebellar
structure and function in IPD and MSA have yet to be fully elucidated.
In terms of functional distinction, the cerebellum is divided into a
“motor” region that includes lobules V, VI, VIIb, and VIII and a “cog-
nitive” region that includes crus I and II (Hoover and Strick, 1999; Kelly
and Strick, 2003; O’Reilly et al., 2010; Balsters et al., 2014). Although
the system is more complex than this, the two distinct regions provide a
good basis for investigating the alterations of cerebellar structure and
function (Buckner et al., 2011). Information from the outputs of these
cerebellar regions converges on the dentate nucleus (DN) and then
(
MSA) are common progressive neurodegenerative diseases in the aging
population that manifest with many overlapping motor and non-motor
symptoms, including parkinsonism, cognitive impairment, and auto-
nomic dysfunction (Ramli et al., 2015; Stefanova et al., 2009). It is
unclear which pathophysiological mechanisms are common to both
diseases and which are distinct, leading to difficulty in distinguishing
the conditions from one another as well as understanding MSA patients’
poorer prognosis and lack of suitability for deep brain stimulation
treatment (Wang et al., 2011; Gilman et al., 2008). As an important
player in the cerebello-thalamo-cortical (CTC) circuits involved in
⁎
Correspondence to: First Affiliated Hospital, China Medical University, 155 Nanjing North Street, Shenyang 110001, Liaoning, China.
E-mail addresses: wangna100medical@126.com (N. Wang), 270973226@163.com (L. Zhang), yanghuaguang1@163.com (H. Yang),
liuhu1234567@126.com (H. Liu), grace_shenyang@163.com (X. Luo), fanguog@sina.com (G. Fan).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.neuropsychologia.2018.12.019
Received 19 April 2018; Received in revised form 13 October 2018; Accepted 21 December 2018
0028-3932/ © 2018 Published by Elsevier Ltd.
Please cite this article as: Wang, N., Neuropsychologia, https://doi.org/10.1016/j.neuropsychologia.2018.12.019

N. Wang et al.
Neuropsychologia xxx (xxxx) xxx–xxx
projects to the striatum, completing the functional integration between
the basal ganglia and cerebellum and comprising part of the cerebellar-
cerebral circuits (Kelly and Strick, 2003; Middleton and Strick, 2000). A
previous study showed disrupted DN-cerebellar functional connectivity
their detailed medical history, no participant had a history of neuro-
logical surgery, substance abuse or dependence, endocrine disease,
diabetes mellitus, hypertension, or thyroid disease. No history of neu-
rological illness was reported in the HC, and no co-occurring neurolo-
gical illnesses were detected in the IPD and MSA patients. Each of the
subjects was right-handed without any contraindications for MRI.
In all, 159 individuals participated in this study, including 38 IPD
patients, 62 MSA patients, and 59 age-, gender-, and education-matched
HC. HC were recruited from the community by advertisement. Patients
were enrolled from the neurology outpatient clinic at the First Affiliated
Hospital of China Medical University, Shenyang, China, with at least a
1-year follow-up to reconfirm diagnosis. IPD patients met the UK PD
Society Brain Bank diagnostic criteria and the requirements for receipt
of deep brain stimulation (Hughes et al., 1992). MSA patients were
diagnosed as “probable MSA”, which fulfills the most stringent criteria
for MSA diagnosis according to the second consensus clinical criteria
(Gilman et al., 2008). All participants took their last dose of anti-
parkinson medication approximately 12 h prior to the MRI scan (i.e.,
during the “off state”). A battery of neuropsychological tests that in-
cluded the Mini-Mental State Examination (MMSE) and MoCA was
performed. Movement ratings were composed of the Unified Parkin-
son's Disease Rating Scale (UPDRS-III) and Hoehn and Yahr (H-Y) stage.
HC did not show cognitive decline based on a MoCA score > 26 or >
25 for secondary school (12 years of education).
(
FC) and DN-default mode network (DMN) FC in IPD relative to healthy
controls (HC), and it was suggested that there may be a compensatory
cerebellar connectivity mechanism at play (Liu et al., 2013). In another
study, the authors used the right cerebellar hemisphere as the region of
interest (ROI) and observed that the enhanced cerebellar-whole brain
FC and stronger FC within the cerebellum was related to better per-
formance in IPD patients (Festini et al., 2015). In contrast, another
study found that greater FC (i.e., between the right crus II and right crus
I and cerebellar-whole brain FC) was related to worse Montreal Cog-
nitive Assessment (MoCA) scores and disease severity, which suggests
pathological cerebellar processes in the IPD group (Mirdamadi, 2016).
The inconsistent findings regarding the role of the cerebellum in IPD
indicate that further research is needed, and to aid in clarification, the
DN could be considered as the ROI. Additionally, very limited resting-
state functional magnetic resonance imaging (rs-fMRI) approaches have
been performed to explore brain activity in MSA. Previous studies
found that cerebellum and cortical region hypoperfusion and hypo-
metabolism were associated with cognitive decline, disease severity and
duration in MSA patients (Lee et al., 2008; Kawai et al., 2008). A po-
sitron emission tomography study found a disease-specific pattern of
significantly decreased metabolic activity in the cerebellum and pu-
tamen in MSA (Laura et al., 2010). Moreover, robust positron emission
tomography evidence showed significant extensive hypometabolism in
the basal ganglia, frontal lobe and the cerebellum of MSA patients
compared with HC and IPD (Feng et al., 2008). Taken together, these
results indicate that alterations in cerebellar function may show both
differences and similarities between IPD and MSA and warrant a
comparative study.
2.2. Rs-fMRI image acquisition
The imaging data were obtained using a 3.0 T MRI scanner
(Magnetom Verio, Siemens, Erlangen, Germany) equipped with a 32-
channel head coil in the Department of Radiology. Each participant was
instructed to rest with their eyes closed but to stay awake. We routinely
confirmed that none of the patients had fallen asleep immediately fol-
lowing the scan.
Recently, grey matter volume (GMV) has been viewed as an im-
portant driving factor in changes to FC, and the association between
GMV and FC may allow for us to explore and validate the relevant
functional components (O'Callaghan et al., 2016; Atluri et al., 2013). A
recent study found that significant changes in FC between the cere-
bellum and large-scale cortical networks, including decreases in sen-
sorimotor and DMN, were related to cerebellar atrophy in IPD patients
Anatomical imaging included a high-resolution three-dimensional
sagittal magnetization-prepared rapid acquisition gradient echo T1-
weighted sequence with the following parameters: repetition time
̊
(TR) = 5000 ms, echo time (TE) = 2960 ms, flip angle = 12 , field of
2
view (FOV) = 256 × 256 mm , matrix size = 256 × 256, slice thick-
(
O'Callaghan et al., 2016). Other studies have found that local cere-
ness = 1 mm, no slice gap, voxel size = 1.0 × 1.0 × 1.0 mm, and slice
number = 176. The resting-state functional images were acquired
using a single-short gradient-echo echo-planar imaging sequence par-
allel to the anterior commissure-posterior commissure plane with the
bellar atrophy plays a role in alterations of FC in healthy aging and in
other diseases (Kalpouzos et al., 2012; Maillet and Rajah, 2013).
Moreover, both motor and cognitive cerebellar GMV were reduced in
the IPD and MSA groups compared to HC, and cerebellum thinning was
observed in the MSA group relative to HC (Kim et al., 2015; Lee et al.,
̊
following parameters: TR = 2500 ms, TE = 30 ms, flip angle = 90 ,
2
FOV = 224 × 224 mm ,
matrix
size = 64 × 64,
slice
thick-
2
015). Other studies also found that GMV in IPD may be less pro-
ness = 3.5 mm, no slice gap, voxel size = 3.5 × 3.5 × 3.5 mm, and
slice number = 43.
nounced than in MSA (Paviour et al., 2006; Massey et al., 2012) Sur-
prisingly, there has been little research into whether alterations of
cerebellar GMV are significantly different between IPD and MSA pa-
tients and whether there is a different association between cerebellar
GMV and alterations of cerebellar FC in the two patient groups.
We conducted voxel-based morphometry analysis (VBM) to explore
cerebellar GMV and selected the DN as the ROI to investigate ab-
normalities of cerebellar FC in IPD and MSA. We predicted that IPD and
MSA would show similar patterns of alterations in cerebellar GMV and
FC compared with HC but with more widespread regional changes in
the MSA group. We also hypothesized that cerebellar GMV would be
associated with FC.
2.3. VBM analysis preprocessing
The processing of the structural neuroimaging data was performed
on the 3D T1-weighted scans using DARTEL algorithm Statistical
Parametric Mapping software (SPM8, http://www.fil.ion.ucl.ac.uk/
spm/software/spm8/) under the MATLAB R2010b platform
(Mathworks, Sherborn, MA, USA). The preprocessing of the data first
involved segmentation, where the regions were divided into GM, white
matter, and cerebrospinal fluid using the “new segment” tool that was
implemented in SPM8. Intersubject registration was achieved using
respective registration based on group assignment in a spatial normal-
ization step. A modulation step ensured that the overall amount of
tissue in a class was unaltered. The segmented images were then nor-
malized to the Montreal Neurological Institute template and smoothed
with an 8-mm full-width at half-maximum Gaussian filter. The acquired
voxel size of 1 mm3 was normalized to 1.5 × 1.5 × 1.5 mm .
2
. Materials and methods
2.1. Participants
The present study was approved by the Institutional Review Board
3
of China Medical University. Informed consent with a detailed de-
scription of the study was signed by each of the participants. Based on
2

N. Wang et al.
Neuropsychologia xxx (xxxx) xxx–xxx
2
.4. Rs-fMRI data preprocessing
among the diagnostic groups, with age and gender as covariates, using
SPM8. Comparisons among patient groups and HC were performed in
the cerebellar mask. A cerebellar mask was defined using a validated
probabilistic atlas of the human cerebellum available in the SUIT
toolbox (Diedrichsen et al., 2009). A significant main effect among
groups was determined at the voxelwise and cluster level of p < 0.001,
corrected via familywise error correction. Then, a post hoc analysis was
conducted to analyze between-group differences within a mask pre-
senting statistical significance in the full-factorial design results and
shared similar covariates (MSA vs. HC, IPD vs. HC, MSA vs. HC,
p < 0.001).
The fMRI data were processed with SPM8 and Data Processing &
Analysis of Brain Imaging (DPABI) software (http://rfmri.org/dpabi).
The first 10 volumes of scanned data for each participant were dis-
carded to avoid magnetic saturation effects. The following steps were
conducted to preprocess the remaining images: slice timing, head mo-
tion correction, spatial normalization to the standard Montreal
3
Neurological Institute space, resampling into 3 × 3 × 3 mm voxels,
and spatial smoothing with a Gaussian filter of 6 mm full-width at half-
maximum. Subsequent preprocessing consisted of removing linear drift
through linear regression and temporal bandpass filtering
Statistical analysis of FC data was performed using DPABI software.
One-way ANOVA with age, gender, and mean framewise displacement
values (FD) as covariates was performed to explore FC differences
among the three groups within the whole brain mask. Subsequently, we
used post hoc tests to analyze between-group differences within a mask
presenting statistical significance in the ANOVA results and shared si-
milar covariates and a multiple comparison correction method with
ANOVA (MSA vs. HC, IPD vs. HC, MSA vs. HC, AlphaSim correction,
p < 0.001).
(
0.01–0.08 Hz) to reduce the effects of low-frequency drift and phy-
siological high-frequency noise. To remove the effects of nuisance
covariates, linear regression of the head motion parameters, white
matter signals and cerebrospinal fluid signals was performed.
According to the realignment parameters of fMRI run head motion,
subjects were excluded from future analysis if they showed motion of
greater than 2.5 mm maximum displacement in any of the x, y, or z
directions or more than 2.5° of angular motion during the scan.
The GMV and FC values of each patient group were extracted within
the clusters presenting statistical significance in the full-factorial design
results and in the ANOVA results. The extracted values of GMV for each
subject were averaged to create a mean value that represented the ex-
tent of average cerebellar atrophy for each individual. Correlations of a
mean value of cerebellar GMV and FC defined above were assessed
using partial correlation analyses with age, gender, and FD as covari-
ates within each patient group (Bonferroni correction). In addition, a
composite connectivity/atrophy score was calculated (created by mul-
tiplying the inverse value of the percentage of atrophy in the cere-
bellum by DN FC within each patient group) (O'Callaghan et al., 2016).
The values of the DN FC were extracted within the clusters showing
associations between cerebellar GMV and FC. Then, relationships be-
tween motor/cognition impairment severity (UPDRS-III and MoCA
scores), atrophy, and impaired connectivity were determined using
Spearman's correlation analyses. The results were considered sig-
nificant at p < 0.05.
2
.5. Definition of ROIs
The bilateral DN ROIs were defined according to the WFU_PickAtlas
(
http://www.ansir.wfubmc.edu)
and
were
resampled
to
3
3
× 3 × 3 mm voxels. For each subject, the blood-oxygen level-de-
pendent time series of the voxels within each DN ROI was averaged to
generate the reference time series for this ROI. A whole brain mask was
created using the normalized T1-weighted high-resolution images of all
participants, which were stripped using the software BrainSuite2
(
http://brainsuite.usc.edu). Only voxels within the mask were analyzed
further.
2.6. FC calculation
A voxelwise FC analysis of the ROI was used. Correlation analysis
was performed between each DN ROI and the whole brain mask in a
voxelwise manner using DPABI. The correlation coefficients were
transformed to z-values using the Fisher r-to-z transformation to im-
prove normality.
3. Results
3.1. Demographic and clinical data
2.7. Statistical analysis
No significant differences in age (U = 2.08, p = 0.35), gender
The chi-square test, the Kruskal-Wallis test and the Dunn multiple
(χ2 = 0.27, p = 0.88), and years of education (F = 3.84, p = 0.15)
were found between groups. However, there were significant differ-
ences in MoCA (χ2 = 57.11, p = 0.000) scores (Table 1). The MSA and
IPD groups had significantly lower MoCA scores compared with the HC
group, while no significant difference was found between patient
groups. The MSA group had a significantly shorter duration of illness
comparison test were performed for demographic variables and clinical
data among the MSA, IPD, and HC groups using SPSS 22.0 software
(
SPSS Inc., Chicago, Illinois, USA). The results were considered sig-
nificant at a threshold of p < 0.05.
A full-factorial design was used to compare GMV of the cerebellum
Table 1
Demographic and clinical characteristics.
Characteristics (Mean ± SD)
MSA (n = 62)
IPD (n = 38)
HC (n = 59)
Analysis
U/χ2
p
Age (years)
63.81 ± 8.55
31/31
61.92 ± 8.59
19/19
64.68 ± 4.25
2.08
0.35
Gender (male/female)
Education
27/32
0.27
0.88
10.48 ± 4.45
3.50 ± 2.07
35.42 ± 18.84
2.62 ± 1.03
21.32 ± 4.21*
0.09 ± 0.07
10.43 ± 3.75
5.39 ± 2.89
40.55 ± 15.97
2.28 ± 0.74
22.81 ± 4.73*
0.11 ± 0.11
11.31 ± 2.36
3.84
0.15
Disease duration
UPDRS-III score
Hoehn and Yahr
MoCA score
–
739.5
794.5
2.61
0.002*
0.12
–
–
0.11
26.75 ± 1.30
0.09 ± 0.06
57.11
0.42
0.000*
0.81
FD
Notes: SD, standard deviation; MSA: multiple system atrophy; IPD: idiopathic Parkinson's disease; HC: healthy controls; UPDRS-III: Unified Parkinson's Disease Rating
Scale; MoCA: Montreal Cognitive Assessment; FD: mean frame-wise displacement values; p < 0.05 was considered statistically significant; The star sign was
considered statistically significant between patient group and HC.
3

N. Wang et al.
Neuropsychologia xxx (xxxx) xxx–xxx
Table 2
Brain regions with significant cerebellar GMV differences in the three groups (MSA, IPD, and HC).
Index
Brain region
Cluster size (voxels)
MNI Coordinates
F values
X
Y
Z
1
2
Cerebellum crus II_L (AAL)
Cerebellum crus II_R (AAL)
Cerebellum lobule VI_R (AAL)
Cerebellum crus I_R (AAL)
Cerebellum crus I_L (AAL)
Cerebellum lobule VI_L (AAL)
Vermis_VI (AAL)
1718
2981
−42
42
−58
−60
−45
−45
29.10
21.06
3
4
5
6
7
8
9
460
28
−33
−22
0
−64
−54
−64
−42
−45
−51
−69
−36
−27
−17
−20
−14
−48
−45
−38
−26
15.74
22.98
21.82
17.80
19.46
18.36
17.71
16.43
231
37
Vermis_III (AAL)
2
Cerebellum lobule IX_L (AAL)
Cerebellum lobule IX_R (AAL)
Cerebellum lobule VIII_R (AAL)
Cerebellum lobule IV-VI (AAL)
362
190
76
−10
2
9
1
0
177
−30
(
U = 718.5, p = 0.002) than the IPD group. There was no significant
3.5. Relationship between motor/cognition impairment severity,
connectivity, and cerebellar atrophy
difference between the patient groups in H-Y stage (U = 2.61,
p = 0.11) and UPDRS-III scores (U = 794.5, p = 0.12). No significant
difference in FD values was found among the three groups (U = 0.42,
p = 0.81).
There was an inverse correlation between the MoCA scores and the
extent of cerebellar atrophy and impaired FC between the bilateral DN
and DMN (left: r = −0.255, p = 0.045, right: r = −0.27, p = 0.034),
as well as a positive association between UPDRS-III scores and a com-
posite score of the cerebellar GMV and altered left DN FC in DMN
3
.2. Three-group comparison of cerebellar GMV
(
r = 0.261, p = 0.04) in MSA patients (Fig. 3). No other relationships
A difference in cerebellar GMV was apparent in both cognitive and
between cerebellar atrophy and FC were significantly correlated with
UPDRS-III/MoCA scores in the IPD group.
motor subregions, including the bilateral crus I and II, bilateral lobule
VI, bilateral lobule IX, right lobule VIII, left lobule IV-V and vermis
(
vermis III and VI) among the MSA, IPD and HC groups (Table 2 and
4
. Discussion
Fig. 1). Specifically, GMV in left crus I and II, bilateral lobules VI, bi-
lateral lobules IX, right lobule VIII and vermis was significantly de-
creased in MSA relative to IPD and HC. Compared with HC, GMV in left
lobules IV-V and left lobule VI was reduced in the MSA and IPD groups,
respectively. Moreover, GMV in right crus I and II was reduced in MSA
relative to IPD (Fig. 1).
The present study combined cerebellar GMV and FC approaches to
reveal similarities and differences in the patterns of cerebellar structure
and function between IPD and MSA patients. Our findings revealed si-
milar alterations of cerebellar GMV and FC in both patient groups re-
lative to HC, along with more widespread and severe changes in MSA
that included both GMV of cognitive and motor subregions and DN-
DMN FC. Furthermore, data from the MSA group showed correlations
between decreased cerebellar GMV and impaired intracerebellar and
DN-DMN FC. Meanwhile, lower motor/cognitive scores were associated
with diminished DN-DMN FC with consideration of cerebellar GMV loss
in MSA patients, which may help elucidate correlations between cere-
bellar FC pathways and clinical symptoms.
3
.3. Three-group comparison of FC
FC between the left DN and cerebellum was altered in the right
lobule VIII and the right crus II among the three groups, while no sig-
nificant difference was reported between the right DN and cerebellum.
Compared with the HC group, both patient groups showed decreased
FC between the left DN and cerebellum in right lobule VIII and right
crus II. No significant different was found in FC between the left DN and
cerebellum in the MSA group as compared to the IPD group (Table 3
and Fig. 2).
Many previous studies found cerebellar GMV loss in IPD and MSA
patient groups, and the loss was more prominent in MSA patients (Kim
et al., 2015; Paviour et al., 2006; Massey et al., 2012). Our study
confirmed these reports, showing that cerebellar GMV was reduced in
the motor subregions in both IPD and MSA patients, and MSA patients
exhibited broader alterations in motor and cognitive subregions with
higher overall volume loss. Importantly, cerebellar GMV reduction in
the cognitive subregions might differentiate IPD from MSA. Post-
mortem studies have demonstrated that the mechanisms underlying
MSA cerebellar pathology involve α-synuclein and other proteins
forming glial cytoplasmic inclusions, primarily in the olivopontocer-
ebellar system (Stefanova and Wenning, 2016). Cerebellar neuronal
degeneration was also reported in mouse and monkey models of IPD
The patterns of FC between the bilateral DN and cerebra revealed
significant alterations of the DMN and motor network when comparing
the MSA, IPD, and HC groups with correction for multiple comparisons
(
Supplementary Table e-1 and Fig. 2). In particular, the inferior tem-
poral gyrus, which is a component of the DMN, displayed significantly
decreased bilateral DN-cerebral FC in the MSA group in comparison to
the IPD group (Supplementary Tables e-2 and e-3).
(
Rolland et al., 2007; Stefanova and Wenning, 2016). The reduction of
3
.4. Relationship between cerebellar GMV and resting state FC
cerebellar GMV may be consistent with the pathology results in both
patient groups, while the more severe GMV changes in the motor and
cognitive subregions may indicate a more severe clinical condition in
MSA. However, other studies have failed to produce the same evidence.
For example, a quantitative analysis study found no cerebellar volu-
metric differences within a whole brain mask in IPD relative to HC,
while volume was significantly decreased in MSA compared with IPD
and HC (Messina et al., 2011). Another morphological study found that
There was no significant relationship between cerebellar GMV and
bilateral DN-cerebellar FC for IPD patients. In contrast, in MSA patients,
the cerebellar GMV was associated with altered left DN FC in right
cerebellum lobule VIII and right crus II (r = 0.329, p = 0.011), as well
as bilateral DN-DMN FC (left: r = 0.342, p = 0.008, right: r = 0.35,
p = 0.007) after Bonferroni correction.
4

N. Wang et al.
Neuropsychologia xxx (xxxx) xxx–xxx
Fig. 1. Cerebellar grey matter volume (GMV) differences between
groups. (A) Cerebellar GMV differences among multiple system
atrophy (MSA), idiopathic Parkinson's disease (IPD), and healthy
control (HC) groups. Slice coordinates according to Montreal
Neurological Institute space are shown in the left corner of the slices,
indicating the Z-axis in axial orientation and the X-axis in sagittal
slices. Yellow denotes the regions that differed in the full factorial
results among the three groups. Differences were considered sig-
nificant at a threshold of p < 0.001, corrected via familywise error
correction. (B) and (C) Post hoc comparison of clusters showing sig-
nificant differences in the three groups pairwise analysis (MSA vs. HC,
IPD vs. HC, MSA vs. HC). The clusters of significant difference in the
three-group pairwise analysis correspond to regions listed in Table 2.
*
/**
P
< 0.001.
the cerebellar structure was reduced in both motor and cognitive sub-
regions in the IPD patients, and the changes were more widespread than
those found in our study (O'Callaghan et al., 2016). The present study
was novel in investigating cerebellar GMV differences between IPD and
MSA within a more precise cerebellum mask, a validated probabilistic
atlas of the human cerebellum in the SUIT toolbox, which could
5

N. Wang et al.
Neuropsychologia xxx (xxxx) xxx–xxx
Table 3
Brain regions with significant left DN-cerebellar FC differences between patient groups (MSA, IPD, and HC).
Index
Brain region
Peak coordinates
Cluster size (voxels)
T value
X
Y
Z
ANOVA
1
Cerebellum lobule VIII_R (AAL)
Cerebellum crus II_R (AAL)
MSA Vs. HC
36
–
−63
−60
−63
−54
−54
−51
80
78
29
11.99
1
1
Cerebellum lobule VIII_R (AAL)
Cerebellum crus II_R (AAL)
IPD Vs. HC
36
−4.48
−4.25
Cerebellum lobule VIII_R (AAL)
Cerebellum crus II_R (AAL)
39
improve statistical power compared to a whole brain mask. We spec-
ulate that the differences in findings could have resulted in part from
the broader grey mask and different clinical information (longer disease
duration, etc.) in previous studies compared with our research.
impaired intracerebellar FC may be attributed to a decrease in input
information from the cerebellum, since they found that an inverse re-
lationship between subthalamic nucleus GMV and intracerebellar FC in
HC was lost in IPD patients (O'Callaghan et al., 2016). The difference in
association between GMV and intracerebellar FC between our two pa-
tient groups may provide a clue for exploring the distinct role of cer-
ebellum. In addition, a positive association between cerebellar GMV
and bilateral DN-DMN FC was presented in MSA patients. The DN is the
largest deep nucleus in the human cerebellum and influences cortical
function by relaying output from the cerebellar cortex (Kelly and Strick,
2003). Therefore, altered cerebellar GMV may affect DN-cerebral FC.
Given the pathological alterations to the cerebellum in MSA patients,
these findings may indicate that disrupted DN-DMN FC may be a direct
consequence of local cerebellar GMV loss. In contrast with previous
studies, our results did not show relationships between GMV values of
motor and cognitive subregions and the DN FC in cortical networks in
In the present study, the association between reduced cerebellar
GMV and decreased DN-cerebellum FC differed between the two patient
groups; such an association was detected in both motor and cognitive
regions in the MSA group but not in the IPD group. α-Synuclein protein
accumulation in the cerebellum represents an explicit disease-related
pathological alteration, which may result, at least in part, in the de-
creased output of cerebellar activity in MSA. A previous study revealed
that cerebellar pathological changes may indirectly result in a loss of
GMV and the dysfunction of the CTC pathways in MSA (Stefanova and
Wenning, 2016). However, another study found no relationship be-
tween cerebellar GMV and intracerebellar FC in IPD patients.
(
O'Callaghan et al., 2016). O’Callaghan and colleagues proposed that
Fig. 2. Dentate nucleus (DN) functional connectivity (FC) differences between groups. (A) The left DN FC differences among multiple system atrophy (MSA),
idiopathic Parkinson's disease (IPD), and healthy control (HC) groups. The statistical significance level was set at P < 0.001 and cluster size > 78 voxels within the
whole brain mask, corrected via AlphaSim correction (P < 0.001). (B)The right DN FC differences among MSA, IPD, and HC. The statistical significance level was set
at P < 0.001 and cluster size > 79 voxels within the whole brain mask, corrected via AlphaSim correction (P < 0.001). The clusters of significant difference in the
three-group analysis correspond to regions listed in Table 3 and Supplementary Table e-1. Slice coordinates according to Montreal Neurological Institute space are
shown in the left corner of the slices, indicating the z-axis in axial orientation. Red and yellow denote the regions that differed in FC analysis among the three groups.
6

N. Wang et al.
Neuropsychologia xxx (xxxx) xxx–xxx
Fig. 3. Relationship between motor/cognition impairment severity, connectivity, and cerebellar atrophy in multiple system atrophy. (A) Scatter plot of MoCA scores
and the extent of cerebellar atrophy and impaired functional connectivity (FC) between the bilateral dentate nucleus (DN) and default mode network (DMN). (B)
Scatter plot of UPDRS-III scores and a composite score of the cerebellar GMV and altered left DN FC in DMN.
IPD patients (O'Callaghan et al., 2016). The present study employed a
rigorous correction method in a small simple of IPD patients, which
limited our extraction of cerebellar GMV and thus warrants further
investigation.
studies. Further studies are needed to elucidate changes in cerebellar
function at different diseases stages and should incorporate measures of
structural integrity during on/off states in both IPD and MSA.
There were several limitations to our study. First, previous studies
suggested that levodopa may modulate FC and improve motor perfor-
mance in IPD (O'Callaghan et al., 2016). Although rs-fMRI scanning was
performed in the off-state, we must assess the influence of long-term
antiparkinson medication. The exact effects of primary disease, medi-
cations, and the interactions of these factors should be examined in
future studies (Mirdamadi, 2016). Second, the enrolled patients ranged
from stage 1 to 5, with most in an early-middle stage. Alterations in
brain structure and function tend to be related to disease progression.
Thus, future studies must eliminate these confounding factors by re-
cruiting drug-naïve and short-duration patients or by analyzing on/off
states with a larger sample size to better characterize cerebellar dif-
ferences between MSA and IPD. Third, despite the AlphaSim correction
with a threshold of p < 0.001 was performed, which should be used
with caution and other multiple comparison correction strategies are
needed to replicate the results in the further.
In recent years, growing evidence has suggested that IPD and MSA
are characterized by the dysfunction of the nigrostriatal dopaminergic
pathway and the CTC pathway (Liu, 2013; Stankovic, 2014;Stefanova
and Wenning, 2016). Although no study has explored altered cerebellar
FC in MSA patients, a regional homogeneity study found abnormalities
in local brain activity in motor cortex regions (You et al., 2011). A large
number of rs-fMRI studies and meta-analyses demonstrated that ab-
normalities in brain activity in IPD and MSA patients are primarily
localized to the motor network and DMN (Pan et al., 2017; You et al.,
2
011). The basal ganglia, premotor cortex, precentral gyrus, postcentral
gyrus, supplementary motor area, and cerebellum are the components
of the two pathways and that are identified as motor network (Pan
et al., 2017). Specifically, the basal ganglia and the cerebellum are
connected reciprocally to form an integrated functional network that
influences motor cortical activity (Buckner et al., 2011). The DMN is
composed of multiple brain regions and possesses several functional
specializations, including higher-order cognition, action, emotion, in-
teroception, and perception (You et al., 2011). Consistent with previous
studies and with our hypothesis, our study found decreased FC between
the DN and both motor network and DMN in the IPD and MSA patients,
while MSA showed more widespread alterations in DMN. Furthermore,
decreased cerebellar GMV and impaired DN-DMN FC were negatively
and positively correlated with the MoCA scores and the UPDRS-III
scores, respectively, in the MSA group, which indicates that more se-
vere reduction of GMV and FC could contribute to more severe cogni-
tive and movement-related symptoms. Cerebellar pathology could re-
sult in GMV reduction, and altered FC may be a consequence of GMV
loss in the MSA group. Given the function of cerebellum and the DMN,
the decreased GMV and FC could reflect the pathological role of cere-
bellar alterations in motor and cognitive impairments. Moreover, the
widespread alteration of cerebellar GMV and FC in the MSA patient
group compared to the IPD group may improve our understanding of
the more severe clinical symptoms experienced in MSA.
In conclusion, similar alterations of cerebellar GMV and in-
tracerebellar and DN-cerebral FC patterns were observed in the IPD and
MSA groups. More widespread impairment of motor and cognitive
cerebellar GMV and DN-DMN FC were found in MSA compared with
IPD, which may be attributed to differences in the underlying neural
substrate and may help explain the faster clinical course and poorer
prognosis in MSA. In addition, decreased intracerebellar and DN-DMN
FC was associated with cerebellar GMV loss in the MSA group but not in
the IPD group, which highlights the need for further exploration into
the distinct role of the cerebellum in both diseases. Taking the reduced
cerebellar GMV into consideration, a decrease in DN-DMN FC was re-
lated to motor and cognitive symptoms in MSA group. Together, these
findings emphasize the role of the cerebellum in both IPD and MSA
patient groups and highlight more substantial alterations to GMV and
FC in MSA. We also found possible differences in the GMV of the cog-
nitive cerebellum and in the association between cerebellar GMV and
FC, requiring a more extensive study with a larger sample size among
different illness stages to improve our understanding of the differences
between MSA and IPD.
Many other rs-fMRI studies have suggested that increased activity in
the cerebellum represents a compensatory effect to normalize and cir-
cumvent hypoactivity in the striato–thalamo-cortical motor circuitry in
IPD patients (Mirdamadi, 2016). However, our study showed decreased
cerebellar FC in the off-state. It is possible that the decreased cerebellar
FC had improved in those patients but represented a level that was still
reduced compared to controls. In addition, previous studies confirmed
that cerebellar FC patterns are influenced by global dopamine levels
and cerebellar input signals (O'Callaghan et al., 2016). Our patient
samples experienced a longer duration of illness as well as severe motor
and cognitive impairments, which could have been affected profoundly
by medication and GMV. Hence, decreased FC of the cerebellum might
be attributed to clinical characteristics that differed from previous
Appendix A. Supporting information
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.neuropsychologia.2018.12.019.
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