Entorhinal Cortex Atrophy in Early, Drug-naive Parkinson’s Disease with Mild Cognitive Impairment
Xiuqin Jia1, Zhijiang Wang2,3,4, Tao Yang5, Ying Li6, Shuai Gao1, Guorong Wu7, Tao Jiang1,*, Peipeng Liang8,*
1Department of Radiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. 2Institute of Mental Health, Peking University Sixth Hospital, Beijing 100191, China. 3National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing, China. 4Beijing Municipal Key Lab for Translational Research on Diagnosis and Treatment of Dementia, Beijing, China. 5Department of Psychology, Tsinghua University, Beijing, China. 6Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. 7Department of Radiology and BRIC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. 8School of Psychology, Capital Normal University, Beijing, China.
Patients with Parkinson’s disease (PD) generally have a higher proportion of suffering from mild cognitive impairment (MCI) than normal aged adults. This study aimed to identify the specific neuroanatomical alterations in early, drug-naive PD with MCI (PD-MCI) by comparing to those PD with normal cognition (PD-NC) and healthy controls (HCs), which could help to elucidate the underlying neuropathology and facilitate the development of early therapeutic strategies for treating this disease. Structural MRI data of 237 early, drug-naive non-demented PD patients (classified as 61 PD-MCI and 176 PD-NC) and 69 HCs were included from Parkinson's Progression Markers Initiative (PPMI) database after data quality control. Within these data, a subset of 61 HCs and a subset of 61 PD-NC who were matched to the 61 PD-MCI group for age, gender, and education-level were selected to further eliminate the sample size effect. The gray matter (GM) volume changes between groups were analyzed using voxel-based morphometry (VBM). Furthermore, correlations between GM volume alterations and neuropsychological performances and non-cognitive assessments (including olfactory performance) were further examined. Compared to HC, patients with PD-NC and PD-MCI commonly exhibited atrophies in the bilateral amygdala (AM) and the left primary motor cortex (M1). Patients with PD-MCI exclusively exhibited atrophy in the right entorhinal cortex (ENT) compared to PD-NC. Significantly negative correlations were found between GM loss in the bilateral AM and olfactory performance in all PD patients, and between ENT loss and memory performance in PD-MCI. The findings suggest that the right ENT atrophy may subserve as a biomarker in early, drug-naive PD-MCI, which shed light on the neural underpinnings of the disease and provide new evidence on differentiating the neuroanatomical states between PD-MCI and PD-NC.
Table 1 Demographic and neuropsychological characteristics.
Figure 1. Flow chart of MRI data inclusion and quality control. (A) for PD; (B) for HC.
HC (n = 61)
PD-NC (n = 61)
PD-MCI (n = 61)
MDS-UPDRS Part III
Disease duration (month)
HVLT-R immediate recall#
HVLT-R delayed recall
Semantic fluency total
5.21 ± 2.60
7.90 ± 3.80
10.38 ± 6.07
Table 2 Demographic and neuropsychological characteristics of the subsets of HCs and PD-NC matched in age, gender, and education with PD-MCI.
Figure 2. ANCOVA results of GM alterations among the three groups. (A) for all subjects; (B) for the subsets of groups with sample size matched.
Figure 3. GM atrophy in the bilateral amygdala (AM) (A) and left primary motor cortex (M1) (B) common to PD-NC and PD-MCI. The bar charts show the mean GM volume in each ROI. The scatterplots indicate the positive correlation between volumes in the bilateral AM and olfactory function measured by UPSIT adjusted for age, gender, education level, TIV and GDS score in each ROI in combined PD patients. ** represents p < 0.01 and *** represents p < 0.001.
Cluster size (voxel)
MNI (x, y, z)
-27, 0, -17
29, 3, -17
-44, -20, 41
HC > PD-NC
-29, 0, -17
30, 3, -17
-42, -21, 41
HC > PD-MCI
-26, 0, -17
26, 3, -18
-45, -18, 41
-27, 0, -17
29, 3, -18
-45, -18, 41
PD-NC > PD-MCI
15, -9, -24
Table 3 Clusters of significant gray matter alterations among the three groups.
Cluster size (voxel)
MNI (x, y, z)
-27, 2, -17
23, 2, -24
-44, -20, 41
HC > PD-NC
-29, 2, -17
-42, -20, 39
30, 3, -17
HC > PD-mci
-27, 2, -17
23, 3, -24
-44, -20, 42
-29, 2, -17
-44, -20, 39
30, 3, -17
PD-NC > PD-MCI
12, -6, -24
Table 4 Clusters of significant GM alterations among the subsets of groups.
Figure 4. Right entorhinal cortex (ENT) atrophy specific to PD-MCI. The bar charts show the mean GM volume in the ENT. The scatterplots indicate the positive correlation between ENT volumes and memory performance measured by HVLT-immediate recall adjusted for age, gender, education level, TIV, and GDS score in PD-MCI patients. **, represents p < 0.01.
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