Clinical profiles of patients with PD-MCI and PD-CN
The demographic and clinical profiles of patients with PD are summarised in Table 1. A total of 13 patients were classified as MCI (PD-MCI); 15 patients were classified as cognitively normal (PD-CN). The UPDRS motor scores of the patients with PD-MCI were significantly higher than those of the patients with PD-CN (F(26)=13.542, P< 0.001). Age, Hoehn and Yahr stage, and disease duration did not differ between groups (Age: F(26)=1.922, P= 0.177, Hoehn and Yahr stage: F(26)=0.039, p= 0.844, disease duration : F(26)=0.097, P= 0.758). There were no differences among the groups in daily doses of LDOPA (F(26)=0.669, P= 0.421), total LDOPA and LDOPA equivalent daily dose of dopamine agonist (LEDD) (F(26)=0.018, P= 0.895). In the comparisons of global cognition, there were no group difference in MMSE scores (F(26)=2.992, P=0.096); however, the MoCA scores were significantly lower in the patients with PD-MCI in those with PD-CN (F(26)=8.879, P= 0.006). In comparisons of neuropsychological subdomains, scores on the PASAT, AVLT, and Verbal Fluency Test were lower in the patients with PD-MCI in those with PD-CN (PASAT: F(26)=6.906, P= 0.014, AVLT: F(26)=10.381, P= 0.003, Verbal Fluency Test: F(26)=8.469, P= 0.007). Patients with PD-MCI took a significantly longer time to complete the TMT-A and TMT-B (TMT-A: F(26)=12.243, P= 0.002, TMT-B: F(26)=28.155, P< 0.001).
Table 1. Baseline characteristics of the patients with PD-MCI and PD-CN
|
PD-MCI
|
PD-CN
|
|
|
n = 13
|
n = 15
|
P value
|
|
|
|
|
Age
|
69.4 ± 2.8
|
67.3 ± 4.6
|
N.S.
|
Men
|
8
|
10
|
N.S.
|
Disease Duration (year)
|
5.0 ± 3.2
|
5.4 ± 3.5
|
N.S.
|
HY stage
|
2.1 ± 0.8
|
2.1 ± 0.7
|
N.S.
|
UPDRS part3
|
19.8 ± 8.6
|
10.1± 5.2
|
P < 0.01
|
LDOPA (mg)
|
262 ± 153
|
223 ± 90
|
N.S.
|
LEDD (mg)
|
296 ± 199
|
287 ± 151
|
N.S.
|
MMSE
|
26.9 ± 1.8
|
28.1 ± 1.9
|
N.S.
|
MoCA
|
21.1 ± 3.0
|
24.3 ± 2.8
|
P < 0.01
|
TMT-A (second)
|
65.6 ± 21.0
|
43.8 ± 11.2
|
P < 0.01
|
TMT-B (second)
|
276 ± 107.5
|
111 ± 50.4
|
P < 0.001
|
PASAT
|
21.2 ± 6.1
|
27.2 ± 6.2
|
P < 0.05
|
AVLT (delayed recall)
|
5.5 ± 3.2
|
9.1 ± 2.9
|
P < 0.01
|
Verbal fluency (words)
|
12 ± 2.9
|
15.5 ± 3.1
|
P < 0.01
|
Duration: Disease duration; HY stage: Hoehn and Yahr stage; UPDRS motor: motor sections of united PD rating scale; LEDD: L-dopa equivalent daily dose of dopamine agonist. Calculation of LDDD for each patient was based on theoretical equivalence to L-dopa as follows: L-dopa dose + L-dopa dose × 1/3 [if on entacapone + bromocriptine (mg) ×10 + cabergoline or pramipexole (mg) ×67 + ropinirole (mg) ×20 + pergolide (mg) ×100 + apomorphine (mg) ×8]. MoCA, Montreal Cognitive Assessment, PASAT, Paced Auditory Serial Addition Test; AVLT, Delayed recall of Auditory Visual Learning Test; N.S., not significant
Visuospatial n-back test
The reaction times and correct answer rates for all 3 tests are summarised in Fig 2. The reaction times of all n-back tests were significantly longer in the patients with PD-MCI, compared with the PD-CN (0-back: F(26)=7.873, P=0.009, 1-back: F(26)=4.348, P=0.047, 2-back: F(26)=4.792, P=0.038). In the correct answer rate, there was a significant difference in the score of 2-back test (F(26)=6.001, P=0.021). Scores on the 0-back and 1-back tests were not different between the groups (0-back: F(26)=2.519, P=0.121; 1-back: F(26)=3.013, P=0.094).
Fig 2. Performance of the visuospatial n-back test
- The figure shows rates of correct answers for the patients with PD-CN and PD-MCI. The scores on the 0-back test did not differ significantly between groups. The scores on the 2-back test of PD-MCI were significantly lower than that of PD-CN.
- The figure shows the response time to press correct button. The patients with PD-MCI took significantly longer time to respond.* P<0.05, ** P<0.01
Correlation between scores on the n-back test and other factors
The correlations between scores on the n-back test and other factors are presented in Table 2. There was a significant negative correlation between the scores on the 1-back test and the score on UPDRS Part 3 (R=-0.41, P<0.05) and between the scores on the 2-back test and the score on UPDRS Part 3 (R=-0.42, P<0.05). Additionally, we found positive correlations between scores on MoCA and the 1-back test (R=0.39, P<0.05), as well as between scores on MoCA and the 2-back test (R=0.41, P<0.05). We also found a negative correlation between scores on the TMT-B and the 0-back test (R=-0.50, P<0.01), however, there was no correlation between scores on TMT-A and any load of the n-back test.
Table 2. Correlations between scores on the n-back test and other factors
|
|
0-back
|
1-back
|
2-back
|
PASAT
|
TMT-B
|
|
|
|
|
|
|
|
MoCA
|
Peason' R
|
|
0.39
|
0.413
|
0.35
|
−0.54
|
|
p value
|
N.S.
|
0.040
|
0.029
|
0.041
|
0.003
|
|
|
|
|
|
|
|
TMT-A
|
Peason' R
|
|
|
|
|
0.524
|
|
p value
|
N.S.
|
N.S.
|
N.S.
|
N.S.
|
0.004
|
|
|
|
|
|
|
|
TMT-B
|
Peason' R
|
−0.495
|
−0.5
|
|
−0.5
|
1
|
|
p value
|
0.007
|
0.007
|
N.S.
|
0.007
|
|
|
|
|
|
|
|
|
UPDRS part3
|
Peason' R
|
|
-0.406
|
-0.415
|
−0.406
|
0.685
|
|
p value
|
N.S.
|
0.032
|
0.028
|
0.032
|
0.001
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
N.S.: not significant
fMRI
The fMRI group analyses were performed to compare the patients with PD-MCI and the patients with PD-CN. MNI coordinates of the centre of activation and cluster size for significant findings are summarised in Table 3. For the 0-back test, the PD-MCI group presented significantly reduced brain activation within the right inferior frontal gyrus, left superior frontal gyrus and left medial frontal gyrus. For the 1-back test, significant differences between the groups were observed for right IFG, bilateral superior parietal lobule and bilateral cuneus. For the 2-back test, the PD-MCI group presented significantly reduced brain activation within right inferior parietal lobule (IPL), right middle frontal gyrus (MFG), left superior parietal lobule, left lateral globus pallidus, left cerebellar tonsil and left precentral gyrus. For the 2-back versus 0-back condition, the patients with PD-MCI presented reduced activation within the bilateral MFG and IPL, compared to the patients with PD-CN. The images of significant voxels for each load of the n-back test are presented in Fig 3.
Table 3. MNI coordinates of the centre of activation for each load of the n-back test
Brain region
|
Side
|
Cluster size
|
x
|
y
|
z
|
T-value
|
|
|
|
|
|
|
|
0-back test
|
|
|
|
|
|
|
Inferior Frontal Gyrus
|
R
|
395
|
32
|
16
|
−18
|
3.96
|
Superior Frontal Gyrus
|
L
|
357
|
-24
|
40
|
44
|
4.13
|
Medial Frontal Gyrus
|
L
|
250
|
-8
|
48
|
10
|
3.45
|
|
|
|
|
|
|
|
1-back test
|
|
|
|
|
|
|
Inferior Frontal Gyrus
|
R
|
847
|
28
|
20
|
−22
|
3.99
|
Superior Parietal Lobule
|
R
|
820
|
30
|
−52
|
56
|
3.98
|
Inferior Semi-Lunar Lobule
|
L
|
714
|
−18
|
−64
|
-36
|
4.14
|
Cuneus
|
R
|
654
|
14
|
−82
|
26
|
4.11
|
Middle Occipital Gyrus
|
R
|
543
|
44
|
−82
|
16
|
3.78
|
Superior Temporal Gyrus
|
L
|
487
|
−44
|
−40
|
10
|
4.30
|
Cuneus
|
L
|
422
|
−12
|
−86
|
28
|
4.00
|
Fusiform Gyrus
|
R
|
353
|
42
|
−44
|
−16
|
3.84
|
Superior Parietal Lobule
|
L
|
342
|
−30
|
−50
|
52
|
3.32
|
|
|
|
|
|
|
|
2-back test
|
|
|
|
|
|
|
Inferior Parietal Lobule
|
R
|
2008
|
40
|
−48
|
46
|
4.72
|
Middle Frontal Gyrus
|
R
|
1602
|
44
|
24
|
36
|
4.49
|
Middle Frontal Gyrus
|
R
|
753
|
38
|
46
|
−14
|
4.32
|
Superior Parietal Lobule
|
L
|
752
|
−28
|
−50
|
46
|
3.91
|
Lateral Globus Pallidus
|
L
|
643
|
−24
|
−8
|
2
|
3.92
|
Cerebellar Tonsil
|
L
|
457
|
−30
|
−62
|
−38
|
3.12
|
Precentral Gyrus
|
L
|
436
|
−62
|
14
|
8
|
4.78
|
|
|
|
|
|
|
|
2-back test–0-back test
|
|
|
|
|
|
|
Inferior Parietal Lobule
|
R
|
1031
|
52
|
-36
|
40
|
3.74
|
Middle Frontal Gyrus
|
L
|
810
|
−32
|
22
|
32
|
4.27
|
Middle Frontal Gyrus
|
R
|
621
|
28
|
16
|
56
|
3.85
|
Middle Frontal Gyrus
|
R
|
386
|
42
|
22
|
40
|
3.80
|
Inferior Parietal Lobule
|
L
|
320
|
−36
|
−54
|
38
|
3.49
|
Middle Occipital Gyrus
|
R
|
312
|
26
|
−72
|
6
|
3.91
|
|
|
|
|
|
|
|
Coordinates x, y and z refer to the anatomical location of the Montreal Neurological Institute space for local maxima of clusters.
Fig 3. fMRI analyses comparing PD-MCI and PD-CN
The figure shows the results for the 0-back test (A), 1-back test (B) and 2-back test (C). The coloured regions indicate significantly lower brain activation in PD-MCI, as compared with PD-CN. All the images presented at P < 0.01 (uncorrected) with cluster size >50 voxels in analysis.
The correlations between the scores on the n-back test and task-related activation are shown in Fig 4. We found a positive correlation between the score on the 2-back test within the right IPL and the scores on the 1-back test within superior parietal lobule and MFG.
Fig 4. Correlation analyses
- The image shows the correlation between the scores on the 1-back test and activation of the 1-back test.
- The image shows the correlation between the scores on the 2-back test and activation of the 2-back test.