¶ Information about the Alzheimer's Disease Neuroimaging Initiative is provided in the Acknowledgments.
The authors have declared that no competing interests exist.
Conceived and designed the experiments: ZJY BH CJL LNZ MJ. Analyzed the data: ZJY BH CJL. Contributed reagents/materials/analysis tools: ZJY BH CJL. Wrote the paper: ZJY BH CJL MJ.
In recent years, amnestic mild cognitive impairment (aMCI) has attracted significant attention as an indicator of high risk for Alzheimer's disease. An understanding of the pathology of aMCI may benefit the development of effective clinical treatments for dementia. In this work, we measured the cortical thickness of 109 aMCI subjects and 99 normal controls (NC) twice over two years. The longitudinal changes and the cross-sectional differences between the two types of participants were explored using the vertex thickness values. The thickness of the cortex in aMCI was found significantly reduced in both longitudinal and between-group comparisons, mainly in the temporal lobe, superolateral parietal lobe and some regions of the frontal cortices. Compared to NC, the aMCI showed a significantly high atrophy rate in the left lateral temporal lobe and left parahippocampal gyrus over two years. Additionally, a significant positive correlation between brain atrophy and the decline of Mini-Mental State Examination (MMSE) scores was also found in the left superior and left middle temporal gyrus in aMCI. These findings demonstrated specific longitudinal spatial patterns of cortical atrophy in aMCI and NC. The higher atrophy rate in aMCI might be responsible for the accelerated functional decline in the aMCI progression process.
With the increasing size of the aging population, cognitive impairment has become an intractable problem which threatens the activities of daily life. Dementia, a serious form of cognitive impairment, reduces the ability to learn, communicate, reason, retain and recall past experience and may eventually trigger death
MRI studies focus on patterns of cortical atrophy in aMCI in order to identify the earliest changes in the brain associated with AD, and predict which subjects will progress to a diagnosis of AD. Previous studies using the region of interest (ROI)-based MRI volumetric methods have found atrophy of medial temporal lobe structures in MCI
From the above discussions, we can see that most of the previous studies about aMCI focused on the structural changes between aMCI and normal people or aMCI and AD
For the purpose of this analysis we used ADNI subject data that was previously collected across 50 sites in the United States and Canada. Study subjects gave written informed consent at the time of enrollment for imaging and genetic sample collection and completed questionnaires approved by each participating site's Institutional Review Board (IRB), including Albany Medical College, Banner Alzheimer's Institute and Baylor College of Medicine etc. The complete list of ADNI sites' IRBs can be found at the link:
All the subjects used in this study were obtained from the
This study was undertaken on a sample of 109 aMCI subjects (81 males/28 females) and 99 NC (50 males/49 females). Each participant was scanned twice, the baseline scan and again two years later. The exact time interval between two scans in aMCI is 25.1±0.5 months with range of 24.5–26.1 months while the interval is 25.4±0.8 months with range of 24.3–26.7 months in NC. The baseline scan data of aMCI subjects was named MCI_M1 group (age of 75±7 years with range of 55–88 years) while the NC was named NC_M1 group (age of 75±5 years with range of 50–88 years) and the follow-up scan was named MCI_M2 group and NC_M2 group respectively. The MMSE scores of MCI_M1 and MCI_M2 were 27.2±1.8 and 25.6±3.7 and NC_M1 and NC_M2 were 29.2±0.9 and 29.0±1.2.
All the normal controls were still normal aging and all the aMCI subjects recruited were still aMCI according to the criteria of ADNI database for NC and aMCI over two years. Criteria for the diagnostic of NC were 1) no active neurological or psychiatric disorders; 2) some subjects may have had ongoing medical problems yet the illnesses or their treatments did not interfere with cognitive function; 3) normal neurological exam; 4) were independently functioning community dwellers
All anatomical high-resolution T1-weighted images of the whole brain were acquired sagittally on a 1.5-Tesla MRI scanner using a volumetric 3D MPRAGE (3-dimensional magnetization-prepared rapid acquisition gradient echo) sequence with the following parameters: slice thickness, 1.2 mm; echo time (TE), 3.61 ms; repetition time (TR), 3000 ms; flip angle, 8°; matrix size, 192×192; number of slices, 160; field of view, 1.25×1.25 mm.
T1 images of all subjects were preprocessed with the volume and surface pipeline of FreeSurfer (
Statistical analysis was performed with the vertices thickness values obtained in the data preprocessing.
To analyze whether any significant differences (p<0.05) in MMSE scores existed in the longitudinal observation, paired t-tests were carried out between the MMSE scores of two scans in aMCI and NC respectively.
Paired t-tests were also performed in the comparisons of MCI_M1 vs MCI_M2 and NC_M1 vs NC_M2 to test the significant longitudinal differences in cortical thickness. Multiple comparisons were taken into account for the vertex data using a false discovery rate (FDR) correction at a 0.01 level of significance
Significant differences in cortical thickness between aMCI and NC were tested twice using the two-sample t-tests at homologous vertices while controlling for the effect of age and gender. The random field theory (RFT)-based cluster analysis was used to perform the multiple comparison correction in both comparisons of MCI_M1 vs NC_M1 and MCI_M2 vs NC_M2
We also compared the atrophy rate of two years between aMCI and NC. At first, two matrixes of cortical thickness atrophy rate at every vertex were obtained through the cortical thickness of MCI_M1 minus those of MCI_M2 and then NC_M1 minus NC_M2. The data was then regressed to remove the effects of gender and age. Finally the two-sample t-tests were used to test for statistically significant differences in cortical thickness atrophy rate at homologous vertices between the aMCI and NC. The random field theory (RFT)-based cluster analysis was also used here to perform the multiple comparison correction. The significant level and the size for cluster were same as the setting above.
Finally, the Pearson correlation coefficients were used to explore whether there were some relationships between brain atrophy and neural functional decline. We did the same analysis for aMCI and NC separately. Initially we obtained the differences of cortical thickness and the differences of MMSE scores over two years. Then the Pearson correlation between the differences of cortical thickness and the differences of MMSE scores was performed for every vertex. To correct for multiple comparison, a FDR test was performed using a p value of 0.01
We compared the cortical thickness of the two scans over two years at homologous vertices. Significant differences were found in both the MCI_M1/MCI_M2 and NC_M1/NC_M2 comparisons. In the groups two years later (MCI_M2 and NC_M2), cortical thickness on all the significantly different vertices is thinner than those in the baseline scan.
The red/yellow showed the significantly different cortical thickness between the MCI_M1 and MCI_M2 groups. Only significantly reduced cortical thickness was found in the MCI_M2 group. The color bar indicated the vertex-wise p-value which ranged from 0 to 0.01 with the correction for multiple comparisons.
Region name | Vertices size | Maximum t value | Region name | Vertices size | Maximum t value |
Precentral_L | 8263 | 5.7524 | Fusiform_R | 2403 | 4.9885 |
Frontal_Sup_L | 3936 | 5.7314 | Postcentral_L | 6854 | 4.9803 |
Frontal_Mid_L | 6920 | 5.9494 | Parietal_Sup_L | 3312 | 4.9087 |
Frontal_Inf_Oper_L | 2851 | 5.4962 | Parietal_Inf_L | 5543 | 6.3283 |
Frontal_Inf_Orb_L | 2299 | 4.9262 | Parietal_Inf_R | 3435 | 4.3552 |
Rolandic_Oper_L | 2083 | 5.4640 | SupraMarginal_L | 6458 | 6.0695 |
Supp_Motor_Area_L | 4049 | 4.9487 | SupraMarginal_R | 2599 | 4.4784 |
Frontal_Sup_Medial_L | 3705 | 5.5436 | Angular_L | 5220 | 7.4593 |
Frontal_Sup_Medial_R | 2053 | 4.3258 | Angular_R | 2058 | 4.1197 |
Insula_L | 6287 | 7.2763 | Precuneus_L | 6694 | 6.2796 |
ParaHippocampal_L | 3174 | 8.7620 | Temporal_Sup_L | 6426 | 8.5361 |
ParaHippocampal_R | 2441 | 6.0468 | Temporal_Sup_R | 2808 | 5.8012 |
Lingual_L | 2076 | 7.1827 | Temporal_Mid_L | 5486 | 8.5511 |
Occipital_Mid_L | 4788 | 6.9143 | Temporal_Mid_R | 3830 | 4.7491 |
Fusiform_L | 3622 | 7.2777 | Temporal_Inf_L | 4906 | 8.2319 |
Note: vertices size is the number of significantly thin vertices included in the corresponding brain region. Maximum t value is the maximal t value obtained after the paired t-tests in the brain region.
The differences of cortical thickness between the NC_M1 and NC_M2 (
The colorized areas indicated the different cortical thickness between the NC_M1 and NC_M2 groups. The range and degree of atrophy in NC_M2 were sight. The p values of the vertices indicated by the color bar were corrected using the FDR correction.
Region name | Vertices size | Maximum t value |
Precentral_R | 522 | 4.7192 |
Frontal_Inf_Orb_L | 660 | 4.9231 |
Insula_R | 335 | 5.7101 |
ParaHippocampal_L | 762 | 5.1468 |
ParaHippocampal_R | 293 | 5.1316 |
Fusiform_L | 420 | 4.9273 |
SupraMarginal_R | 302 | 4.5670 |
Temporal_Inf_L | 260 | 4.9113 |
Temporal_Sup_R | 1374 | 5.8042 |
Temporal_Pole_Sup_R | 1136 | 5.8857 |
Note: The meaning of vertices size and maximum t value is same as the
At baseline time, aMCI showed significant cortical thinning compared to NC and no thicker brain regions were found in aMCI. Two clusters with thresholds of p<0.05 (RFT corrected) and cluster size>100 vertices were found (
The colorized areas indicated the brain regions with significantly reduced cortical thickness in aMCI compared with NC at baseline time with a correction for multiple comparisons (P<0.05, the cluster-based RFT correction).
Cluster no. | Region name | L/R | Peak MNI coordinates (x,y,z) | Peak t value | Number of vertices in cluster | RFT-corrected p value for cluster |
1 | Frontal_Sup_Orb | R | 8,66,7 | 4.3465 | 58596 | 2.372e-08 |
Olfactory | R | 15,10,−18 | 4.2341 | |||
Cingulum_Post | R | 5,−53,20 | 4.7801 | |||
ParaHippocampal | R | 25,−11,−23 | 6.8813 | |||
Temporal_Pole_Sup | R | 21,2,−36 | 5.9244 | |||
Temporal_Pole_Mid | R | 27,−3,−38 | 6.2989 | |||
Temporal_Mid | R | 48,0,−36 | 5.4139 | |||
Temporal_Inf | R | 43,−2,−46 | 5.5002 | |||
2 | Cingulum_Post | L | −4,−47,12 | 4.8755 | 52428 | 2.372e-08 |
ParaHippocampal | L | −19,−12,−23 | 7.1993 | |||
Temporal_Pole_Sup | L | −24,−1,−40 | 6.4533 | |||
Temporal_Pole_Mid | L | −30,−4,−36 | 6.6325 | |||
Temporal_Sup | L | −50,9,−37 | 5.3053 | |||
Temporal_Mid | L | −60,−19,−13 | 5.8685 | |||
Temporal_Inf | L | −31,−12,−37 | 6.3065 |
Note: Peak t value is the maximum t value in the corresponding region. MNI is the Montreal Neurological Institute. Peak MNI coordinates is the coordinates of the peak vertex based on the MNI brain template.
Two years later, pronounced atrophy was found appearing in two significant clusters while comparing aMCI to NC (
Significant cortical thickness differences were found between aMCI and NC two years after the baseline time. The color bar indicated the cluster-wise p-value with the cluster-based RFT correction.
Cluster no. | Region name | L/R | Peak MNI coordinates (x,y,z) | Peak t value | Number of vertices in cluster | RFT-corrected p value for cluster |
1 | Cingulum_Post | L | −2,−50,15 | 6.1246 | 96260 | 2.177e-08 |
ParaHippocampal | L | −22,−14,−22 | 8.1999 | |||
Temporal_Pole_Sup | L | −24,−1,−40 | 7.4084 | |||
Temporal_Pole_Mid | L | −30,−4,−36 | 7.4984 | |||
Temporal_Sup | L | −51,0,−24 | 6.8052 | |||
Temporal_Mid | L | −60,−2,−22 | 7.2870 | |||
Temporal_Inf | L | −30,−11,−38 | 7.0859 | |||
Frontal_Sup_Medial | L | −20,60,22 | 4.5265 | |||
Angular | L | −49,−63,41 | 4.9026 | |||
2 | Frontal_Sup_Orb | R | 10,66,9 | 4.4252 | 99789 | 2.177e-08 |
Olfactory | R | 17,8,−17 | 5.6264 | |||
Cingulum_Post | R | 4,−53,19 | 6.4628 | |||
ParaHippocampal | R | 25,−10,−24 | 8.0334 | |||
Temporal_Pole_Sup | R | 21,2,−36 | 7.3326 | |||
Temporal_Pole_Mid | R | 27,−3,−38 | 7.6556 | |||
Temporal_Mid | R | 48,1,−36 | 6.9493 | |||
Temporal_Inf | R | 43,−2,−46 | 7.1703 | |||
Temporal_Sup | R | 50,−11,−17 | 6.2965 | |||
Fusiform | R | 37,−21,−31 | 6.6532 | |||
Angular | R | 45,−57,9 | 4.9855 | |||
Precuneus | R | 4,−53,19 | 6.4641 |
Note: The meanings of Peak t value and Peak MNI coordinates are the same as
Compared with the normal controls, the atrophy rate of aMCI appeared more pronounced. We found two significant clusters with threshold of p<0.05 (RFT corrected) and cluster size>100 (
Differences of atrophy rate between aMCI subjects and normal controls were obtained using the random field theory (RFT)-based cluster analysis. The colorized areas represented the between-group differences of atrophy rate, which showed the more serious atrophy in aMCI over two years. The color bar indicated the cluster-wise p-value with the correction for multiple comparisons.
Cluster no. | Region name | L/R | Peak MNI coordinates (x,y,z) | Peak t value | Number of vertices in cluster | RFT-corrected p value for cluster |
1 | Middle temporal gyrus | L | −53,1,−25 | 4.62 | 5913 | 0.00013351 |
Insular cortex | L | −41,−6,0 | 3.57 | |||
Inferior temporal gyrus | L | −48,1,−37 | 4.08 | |||
Superior temporal gyrus | L | −51,2,−25 | 4.59 | |||
Temporopolar area | L | −49,9,−38 | 4.36 | |||
2 | Parahippocampal gyrus | L | −19,−26,−19 | 3.77 | 1227 | 0.031085 |
Note: The meanings of Peak t value and Peak MNI coordinates are same as
For aMCI, the MMSE scores of MCI_M2 were significantly lower than those of MCI_M1 (p = 4.77e-06<0.05). There were no significant differences of MMSE scores between NC_M1 and NC_M2 (p = 0.23>0.05).
The correlation analysis showed no significant results in NC while a significant positive correlation in aMCI was found in brain regions largely corresponding to the regions demonstrating differences in atrophy rate between aMCI and NC (
The correlations at all significant vertices were positive and the color bar indicated the vertex-wise p-value with the FDR correction at a 0.01 level of significance.
Region name | Vertices size | Maximum R value | Region name | Vertices size | Maximum R value |
Temporal_Sup_L | 620 | 0.4887 | Temporal_Mid_L | 1666 | 0.4800 |
Temporal_Pole_Sup_L | 582 | 0.4892 | Temporal_Pole_Mid_L | 429 | 0.4836 |
Note: Maximum R value is the maximal Pearson correlation coefficients in the corresponding brain region.
In this study, the vertex thickness values were used to explore the longitudinal patterns of cortical atrophy in aMCI and NC. The between-group differences of cortical thickness at two time points and atrophy rate over two years between aMCI and NC were compared. Additionally, the correlation between the decline of MMSE scores and the brain atrophy in aMCI and NC was also explored. The main findings of this study were the following four aspects: (i) Cortical thickness differences between baseline and two years later in aMCI and NC, respectively. For aMCI, cortical thinning appeared in the prefrontal gyrus, somatosensory cortex, Wernicke's area and superolateral temporal lobe after two years. In the second set of measurements for NC, atrophy mainly appeared in the left parahippocampal gyrus, right superior temporal gyrus and right superior temporopolar area. (ii) The between-group differences of cortical thickness at baseline time and two years later. At baseline, aMCI showed cortical thinning mainly in parahippocampal gyrus, temporopolar area, left temporal lobe, right middle and right inferior temporal gyrus. Two years later, aMCI demonstrated additional atrophy in angular gyrus, right fusiform gyrus and right superior temporal gyrus. (iii) Atrophy rate differences between aMCI and NC. Compared with NC, aMCI showed higher atrophy rate in left temporal lobe, left temporopolar area, left insula and left parahippocampal gyrus. (iv) Correlation between the decline of MMSE scores and cortical atrophy in aMCI and NC. Correlation analysis showed no significant results in NC while a significant positive correlation in aMCI was found in left superior and left middle temporal gyrus, left superior and left middle temporopolar area.
The longitudinal changes of cortical thickness in aMCI were quite widespread especially in the left hemisphere. The atrophy appeared in the precentral gyrus and prefrontal cortex showed a strong agreement with previous findings related to changes seen in MCI and AD
Longitudinal atrophy in NC was relatively slight in both range and degree compared to aMCI. The atrophy mainly appeared in the left parahippocampal gyrus, right superior temporal gyrus and right superior temporopolar area. These findings showed a strong agreement with previous MRI findings related to changes seen in normal aging
Compared to NC, the aMCI showed significant cortical atrophy at two time points and the atrophy two years later was more pronounced than baseline time. All the atrophic regions existed at the baseline time remained two years later and the atrophy was more serious. Some regions such as angular gyrus, left medial superior frontal gyrus, right fusiform gyrus, right superior temporal gyrus and right precuneus showed significant atrophy after two years.
The most significant regions in both comparisons were parahippocampal gyrus, superior, middle and inferior temporal gyrus, superior and middle temporopolar area. Atrophy in these regions could be found in many previous studies and was considered to be responsible for the decline of corresponding functions in MCI such as language processing, scene recognition, recognition of known faces, sensation of sound and so on
As we can see from above discussions, the atrophy over two years in aMCI appeared generalized in aMCI whilst there are also some slight cortical changes in normal aging. Thus, we could not ignore the effects of aging in spatial atrophy patterns in aMCI. To more intuitively reflect which regions were seriously affected in the progression of aMCI, we compared the atrophy rate between aMCI and NC. As
The superior temporal gyrus has been considered to contain several important structures, such as the primary auditory cortex and Wernicke's area and be responsible for the sensation of sound and the processing of speech so that it can be understood as language
As depicted in
To explore whether there was any relationship between the cortical atrophy and the degree of cognitive impairment, the Pearson correlation analyses and the MMSE scores were used. The results showed that in aMCI the atrophy in left superior and left middle temporal gyrus, left superior and left middle temporopolar area strongly correlated with the decline of MMSE scores (
The relationship between MMSE and cortical atrophy has been noted in a few other studies and most of them focused on the hippocampal atrophy in MCI and AD
In conclusion, our study found significant spatial patterns of cortical atrophy in aMCI and NC over two years. Compared to NC, aMCI showed the faster atrophy rate and a positive correlation between the regional atrophy and the neural functional decline over two years. The abnormal cerebral regions in aMCI especially the acceleratedly atrophic regions may deserve more attention for researchers in order to increase the understanding of the pathology of aMCI. This might help to find an effective clinical treatment to delay the conversion from aMCI to AD.
The authors thank Liang Gao for the help on the data preprocessing. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (