DOI: https://doi.org/10.21203/rs.3.rs-1270746/v1
Amnestic mild cognitive impairment (aMCI) refers to a transitional stage between normal aging and Alzheimer's disease (AD). At present, numerous studies have reported that the functional connectivity between the hippocampus, thalamus, amygdala and other brain regions is abnormal in patients with MCI and AD. However, few studies have investigated hippocampal, thalamic, amygdalar and whole-brain functional connectivity abnormalities.
Here, we recruited 33 patients with amnestic mild cognitive impairment (aMCI) and 33 age- and sex-matched healthy controls (HCs) and chose the hippocampus, amygdala, and thalamus as regions of interest to explore the functional connectivity between the hippocampus, amygdala, thalamus and the whole brain in patients with aMCI.
Using the hippocampus as region of interest, the whole brain functional connectivity analysis showed that the functional connectivity with the left precuneus, the right precuneus, and the parahippocampal gyrus was increased, and the functional connectivity with left anterior cingulate gyrus was reduced compared with the HC group. Using the thalamus as a region of interest, the whole-brain functional connectivity analysis showed that functional connectivity with the fusiform gyrus, left/right inferior occipital gyrus and left middle occipital gyrus was increased. Using the amygdala as a region of interest, whole-brain functional connectivity analysis showed reduced functional connectivity with the right frontal apex, the right central gyrus and left thalamus and the right supplementary motor area.
We found abnormal functional connectivity in patients with aMCI, indicating that it may provide a reliable imaging index for the early recognition and intervention of AD.
Amnestic type mild cognitive impairment (aMCI) refers to a transitional stage between normal aging and Alzheimer's disease (AD)[1] and it has a high probability of evolving toward AD at a rate of 10–15% per year [2] . The main feature of patients with aMCI is deficits in the individual’s memory, language, thinking judgment, emotion recognition, and executive function due to damage in multiple cognitive regions [3][4]. In severe cases, it will lead to loss of social function and even an inability to care for themselves [5]5. Therefore, the precise identification of high-risk patients with aMCI is very important for prevention and intervention in the early stages of AD.
The hippocampus is a part of the default mode network and closely related to individual learning, language and memory [6][7]. Studies reported reduced functional connectivity between the hippocampus and the prefrontal lobe, temporal lobe, parietal lobe, and cerebellum in patients with aMCI; in other brain regions, functional connectivity is increased and is negatively correlated with episodic memory performance, suggesting functional enhancement to compensate for cognitive impairment caused by the functional impairment[8][9][10]. The cognitive impairment associated with AD may have occurred in the aMCI stage[11] . These findings that abnormal hippocampal functional connectivity may be an early manifestation of AD in patients with aMCI may have important practical significance for the early identification and intervention of AD. Therefore, our work attempts to explore abnormalities in hippocampal function, which may have important practical significance for the in-depth study of AD.
The thalamus is the center of subcortical information transmission and processing, and it has extensive connections with the cerebral cortex and subcortical structures[12][13]. Previous studies have confirmed significant connectivity between the thalamus and different brain regions (such as the frontal, temporal, parietal and occipital lobes); for example, thalamus-hippocampus connectivity is an important pathway for memory[14]. Some studies have also provided evidence of impaired connectivity between the medial temporal cortex and thalamus in patients with AD [15]. Zhou Bo and Zhang Xi et al. (2014) [16] hypothesized that compared with baseline, the functional connectivity of the thalamus with the left inferior parietal cortex, putamen, and right posterior cerebellar lobe was decreased in patients with MCI. Based on the previous studies described above, the thalamus is damaged in patients with MCI, but researchers have not clearly determined whether abnormal thalamic function in patients with mild cognitive impairment is related to the onset of AD. Hence, an in-depth exploration of thalamic dysfunction must be conducted in patients with aMCI through brain imaging, which may provide a critical window for the early recognition and intervention of AD.
The amygdala is one of the key regions in the default network and is the basis of the emotion regulation process [17][18]and is related to emotion and cognitive function [19][20] . Studies have documented altered functional connectivity of the amygdala in patients with MCI and AD[21][22], and some researchers have also reported decreased functional activity of the amygdala in patients with AD[23] . The literature described above not only highlights a key role for the amygdala in emotion regulation but also indicates a certain relationship between changes in the function of the amygdala and cognitive impairment in patients with AD. However, few studies have examined the functional connectivity between the hippocampus, thalamus, amygdala and the whole brain in patients with aMCI, and different research methods have produced different research results. Therefore, this study used functional magnetic resonance imaging (fMRI) to further explore this issue, which may have practical clinical value.
Participants
From April 2018 to November 2019, 33 individuals with aMCI and 32 age- and sex-matched healthy controls (HCs) with no physical diseases or history of psychiatric or neurological disorders were recruited from the local community to participate in this study through advertising. All participants ranged in age from 60 to 80 years, and each subject was a right-handed Han Chinese individual with normal who provided written informed consent for inclusion before this study began. The study was approved by the Ethics Committee of the Wuxi Mental Health Center of Jiangsu Province. The diagnosis of aMCI was determined by the consensus of all experienced neurologists according to the published criteria in the study by Petersen[24] and the National Institute on Aging-Alzheimer’s Association.
Inclusion and exclusion criteria
All participants underwent a broad battery of neuropsychological tests: (a) Hachinski score (HIS) to exclude objects with vascular dementia; (b) activities of daily living (ADL) scale to assess the subjects’ daily living abilities, including basic daily living abilities and relatively complex instrumental activities related to daily living; (c) Hamilton depression scale (HAMD) to exclude patients with a cognitive impairment caused by depression; and (d) Alzheimer’s disease assessment scale (ADAS-Cog) to assess the severity of cognitive impairment. All subjects were right-handed.
Inclusion criteria for the aMCI group are described below. According to the diagnostic criteria of Petersen: (i) memory complaint, preferably corroborated by an informant; (ii) objective memory impairment for age; (iii) relatively preserved general cognition for age; (iv) essentially intact activities of daily living; (v) no diagnosis of dementia. The following cutoff values were established for the neuropsychiatric tests described above: (1) HIS<4; (2) 14≤ADL≤19; (3) HAMD<16; (4) 10<ADAS-Cog<16, and (5) MoCA-B<26.
The normal participants were included based on the following criteria: (1) HIS<4; (2) 14≤ADL<16; (3) HAMD <16; and (4) ADAS-Cog<10, MoCA-B≥26. The exclusion criteria for both groups were an age <60 years and a history of psychiatric, neurological, cerebrovascular, or cognitive illness, stroke or other dementia diagnoses to ensure that they were cognitively normal.
Neuropsychological assessment
All subjects underwent clinical interviews, laboratory examinations, and activities of daily living (ADL) tests to assess functional impairment, and the ADAS-Cog was used to assess the severity of cognitive impairment. The Hamilton depression scale (HAMD) was used to exclude patients with a cognitive impairment caused by depression, and the Hachinski ischemic scale (HIS) was used to exclude people with vascular dementia.
MRI Data Acquisition
An MRI examination of participants was performed with a 3.0 T scanner (General Electric Medical Systems, 750 W, America) using a standard eight-channel phased-array head coil to obtain whole brain images of each subject. For the resting-state scan, the heads of all subjects were fixed with sponge padding and subjects were instructed to rest with their eyes closed, not fall asleep, think of nothing particular during the scan time, and continue to breathe normally during scanning. A structural T1-weighted image was acquired using a 3D SPGR sequence with the following parameters: repetition time (TR)=7.7 ms, echo time (TE)=minimum value, flip angle (FA)=11°, field of view (FOV)=256×256 mm2, matrix=256×256, slices=186, slice thickness=1.2 mm, and voxel size of 1×1×1 mm3. Functional data were collected using a gradient-echo echo-planar imaging (EPI) sequence in axial slices parallel to the line through the anterior and posterior commissures with the following parameters: TR=2 s, TE=30 ms, FA=90°, FOV= 224×224 mm2, matrix=64×64, slices=36, slice thickness =3.5 mm, gap=0.7 mm, voxel size of 3.5×3.5×3.5 mm3. The scan lasted for 240 s .
Statistical analyses
Demographic data were analyzed with IBM SPSS software version 26.0. The distributions of continuous variables approximated normality, and thus parametric tests were used. Two-sample t-tests were performed to examine the differences in age and education, while the chi-square test was used to analyze differences in sex. Two-sample t-tests were also used to compare neuropsychological test scale scores, including the HIS score and ADAS-Cog score, MoCA-B score, and the Mann–Whitney U test was used to examine the differences in HAMD scores. The average FC values of brain regions with distinct FC.
Functional connectivity analyses
Resting-state fMRI data from all participants were preprocessed using the Brainnetome fMRI Toolkit (http://brant.brainnetome.org) based on Statistical Parametric Mapping (SPM12, http://www.fil.ion.ucl.ac.uk/spm) and DPARSFA software using the MATLAB2018b platform (MathWorks). Before preprocessing, the first 10 time points were discarded because of the instability of the initial signal and the participant’s adaptation to the situation. All preprocessing steps included (1) slice-timing correction; (2) realignment to the first volume for head motion correction; (3) spatial normalization to a standard EPI template with reslicing to 2 mm cubic voxels; (4) discarding the effects of head motion and other possible sources of artifacts, such as linear drift, six motion parameters, and the mean time series of all voxels within the white matter and cerebrospinal fluid, to further reduce the effects of confounding factors; and (5) temporal filtering (0.01‒0.08 Hz) to reduce the effect of low-frequency and high-frequency noise. A head motion of <2 mm and rotation of < 2.0° were set as thresholds for each subject to minimize head motions. Three spherical regions of interest (ROIs) (radius=6 mm) were centered at the specified coordinates within the hippocampus (-24, -38, -2), thalamus (-36, 30, -14), and amygdala (2, 6, 1) [25].
General demographic and clinical data.
Demographic information was not statistically significantly different except for age (P<0.05); education years and gender were not significantly different (P>0.05). General clinical data, the ischemia index (Hachinski ischemic scale) and ADL score were not statistically significantly different (P>0.05), whereas the Montreal depression scale, ADAS-Cog and Hamilton depression scale (HAMD) scores were statistically significantly different (P<0.05).(see Table 1 )
Analysis of the functional connectivity between the hippocampus and whole brain
Using the hippocampus as a region of interest (Table 2), compared with the HC group, the whole-brain functional connectivity analysis showed that functional connectivity with the left precuneus, right precuneus, parahippocampus, right inferior occipital gyrus, right inferior temporal gyrus, left inferior occipital gyrus, left talar fissure, right middle occipital gyrus, right central sulcus cover, left superior frontal gyrus, left middle occipital gyrus, left angular gyrus, cuneiform lobe, right superior frontal gyrus, left central posterior gyrus, right central posterior gyrus was increased, and functional connectivity with the left anterior cingulate was reduced in participants with aMCI (Figure 1).
Analysis of functional connectivity between the thalamus and whole brain
Using the thalamus as a region of interest (Table 3), compared with the HC group, whole-brain functional connectivity analysis showed that functional connectivity with the fusiform gyrus, left/right inferior occipital gyrus, left middle occipital gyrus, thalamus and right thalamus, left/right caudate nucleus, middle frontal gyrus, right middle frontal gyrus, right supra marginal gyrus, precentral, right central anterior gyrus, postcentral, right superior parietal, and right middle frontal gyrus was increased in patients with aMCI (Fig. 2).
Analysis of functional connectivity between the amygdala and whole brain
Using the amygdala as a region of interest (Table 4), compared with the HC group, the whole-brain functional connectivity analysis showed that functional connectivity with the right superior frontal and right precentral regions was increased, and functional connectivity with the left thalamus and supplementary motor area were reduced in patients with aMCI (Figure 3).
Analysis of functional connectivity between the hippocampus and whole brain
In the present study, compared with the HC group, we observed reduced functional connectivity between the hippocampus and left anterior cingulate. This pattern of alterations was consistent with findings reported in previous studies [26][27][28] and suggested that the hippocampal function of patients with aMCI may also be abnormal. During the transition from MCI to AD, the functional connectivity between the hippocampus and the left cingulate gyrus is decreased, and the cingulate gyrus changes after MCI pathological changes occur in the cortex[29][30]. The posterior cingulate gyrus is very important for predicting the outcome of the transition from MCI to AD and early identification of the disease[31] .Therefore, we speculate that the decrease in functional connectivity between the hippocampus and the left cingulate gyrus of patients with aMCI, which may interrupt or damage the entire default network function integration, and a reduction in connectivity between these two regions plausibly represents an early imaging biomarker for aMCI.
In addition, compared with the HC group, we found increased functional connectivity between the hippocampus and cuneiform lobes, parahippocampal gyrus, upper middle occipital/inferior gyrus, superior frontal gyrus, superior temporal/inferior gyrus, left talar fissure, right central sulcus lid, left angular gyrus, and central posterior gyrus. This finding was consistent with previous studies[32][33] .We propose that the hippocampus and the brain regions listed above may cooperate in information exchange or storage. The increase in functional connectivity between the hippocampus and the brain regions listed above is likely due to the mutual cooperation between the hippocampus and these brain regions in the process of information exchange or storage, resulting in functional compensation in the brain region. The increase in functional connectivity is likely to compensate for the weakening of the function of a certain brain region to balance whole-brain function.
Analysis of functional connectivity between the thalamus and whole brain
Compared to HCs, subjects with aMCI showed increased functional connectivity between the thalamus and fusiform gyrus, left/right suboccipital gyrus, left middle occipital gyrus, thalamus, right thalamus, left/right caudate nucleus, middle frontal gyrus, right middle frontal gyrus, right superior marginal gyrus, anterior central gyrus, right anterior central gyrus, posterior central gyrus and superior paracentral gyrus. The thalamus is an important part of the default network mode. Cappell(2010) 34 [34]postulated that the default network mode of patients with aMCI has a higher mean functional connectivity and may reflect a compensatory mechanism. This mechanism assumes that the overactive region "works harder" to compensate for the decreased function of other parts of the brain. Therefore, we speculate that increased functional connectivity between the thalamus and whole brain may indicate a compensatory mechanism in the brain of patients with aMCI. Previous studies have reported decreased functional connectivity between the bilateral thalamus and frontal cortex in patients with aMCI[35]. This brain region is involved in episodic memory retrieval, emotional processing and executive functions and plays a prominent role in integrating information from multiple cognitive fields [36][37], however, our work did not reveal decreased functional connectivity between the thalamus and other brain regions.
Analysis of functional connectivity between the amygdala and whole brain
After exploring functional connectivity between the amygdala and whole brain, compared with HCs, patients with aMCI showed increased functional connectivity with the right superior frontal and right precentral regions. Preliminary studies also showed amygdala brain function abnormalities in patients with MCI[23], and the amygdala is involved in regulating cognitive functions such as attention, perception, emotional memory, explicit memory and declarative memory[38]. Functional connectivity abnormalities of the superior frontal gyrus and the central anterior gyrus are likely to affect attention-related cognitive functions[39]. Therefore, we hypothesize that the increased functional connectivity of the amygdala may be related to the impairment of cognitive functions, such as emotion regulation and memory consolidation, in the aMCI group, which may also provide possible medical imaging indicators for the early diagnosis of aMCI and promote a better understanding of dementia progression and potentially comprehensive interventions for aMCI. More interestingly, this study also revealed decreased functional connectivity between the amygdala and the left thalamus and right supplementary motor area in patients with aMCI; the sensorimotor cortex was only involved in the later stages of AD in a previous study[40]. We obtained similar evidence of abnormal brain function in the sensorimotor cortex of patients with aMCI, which may be a sign of AD lesions.
We used the hippocampus, amygdala, and thalamus as regions of interest and found abnormalities in the functional connectivity of the brain in patients with aMCI, suggesting that the function of key brain regions in the default mode network are impaired in patients with aMCI. Our findings may provide a better and more thorough understanding of aMCI and AD, as well as a potential predictor and the possibility of comprehensive intervention for patients with aMCI.
This study was approved by the ethics committee of Wuxi mental health center, Approval No:WXMHCIR2015LL010. All methods were performed in accordance with the relevant guidelines and regulations by including a statement in the declarations. And all participants completed the informed consent form.
Ethics approvals
This study was approved by the ethics committee of Wuxi mental health center, Approval No:WXMHCIR2015LL010. All methods were performed in accordance with the relevant guidelines and regulations by including a statement in the declarations. And all participants completed the informed consent form.
Consent for publication
Not applicable
Availability of data and materials
All relevant data and materials of the findings are anonymised and stored at the
Scientific Research Division of the Suzhou Mental Health Center. and the data are available on request from the corresponding author.
"The datasets generated and/or analysed during the current study are not publicly available due [Our data results use matlab to load spm, and then load restplus to open it. At the same time, the capacity of the original data is very large, and there are certain difficulties in uploading] but are available from the corresponding author on reasonable request."
Competing interests
The authors declare no competing non-financial/financial interests.
Funding
This research was supported by Youth Science and technology project of (KJXW2019048) to Dong WANG
Authors' contributions
Fang-wen ZHANG designed the study, collected the data and assisted with writing the article. Teng-long WANG scored the neuroimaging data and supervised data collection. Dong WANG obtained the grant for the study.and was responsible for the statistical design of the study.
Acknowledgments
The authors would like to thank the Department of Psychiatry, Suzhou Mental Health Center, Suzhou Guangji Hospital, the Affiliated Guangji Hospital of Soochow University, and we also thank all of the participants involved in the study.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author details
1 Department of Psychology, School of Public Adminitration, Northwest University, Xi’an 710127, China.
2 The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi, 214151, China.
3 Department of Psychiatry, Suzhou Mental Health Center, Suzhou Guangji Hospital, the Affiliated Guangji Hospital of Soochow University, Suzhou, 215131, China.
Items |
aMCI(n=33) |
NC(n=33) |
t/c2/ MWU |
P value |
---|---|---|---|---|
Age (years), mean (SD) |
68.79 (4.87) |
68.88 (4.92) |
-0.08 |
0.94* |
Male/Female |
18/15 |
19/14 |
0.06 |
0.80** |
Education (years), mean (SD) |
9.24 (2.73) |
10.9 (3.59) |
-2.16 |
0.04* |
HIS score, mean (SD) |
1.48 (0.67) |
1.27±0.94 |
1.05 |
0.30* |
ADL score, mean (SD) |
14.45 (1.15) |
14.03 (0.17) |
2.1 |
0.04* |
HAMD score, median (Q) |
2 (4) |
1 (4) |
361 |
0.01*** |
ADAS-Cog score, mean (SD) |
11.45±1.15 |
7.27±2.98 |
1.05 |
0.00* |
MoCA-B (SD) |
21.79(3.65) |
23.79(3.30) |
2.3 |
0.023* |
Abbreviations: aMCI: amnestic mild cognitive impairment; NC: normal control, MWU, Mann–WhitneyU-test; HIS: Hachinski score;ADL: Activities of daily living scale; HAMD: Hamilton's depression scale; ADAS-Cog: Alzheimer's disease assessment scale‐cognitive subscale; MoCA-B: Montreal Cognitive Assessment -Basic Chinese Version . | ||||
*P values obtained by independent sample t-test. | ||||
⁎⁎P value for sex distribution obtained by Pearson's chi-square test. | ||||
***P values obtained by rank sum test. |
Table 2 Functional connectivity between the hippocampus and whole brain
Seed |
BA |
Cluster size |
|
MNI |
|
Peak intensity |
|
x |
y |
z |
|
||||
Parahippocampal(L) |
36 |
14 |
-18 |
-3 |
-36 |
5.3033 |
MCI>HC |
Precuneus(L) |
31 |
129 |
-24 |
-36 |
-6 |
7.5466 |
|
Precuneus(R) |
31 |
91 |
|
|
|
|
|
Parahippocampal Gyrus |
|
10 |
-30 |
-12 |
-24 |
4.6996 |
|
inferior occipital gyrus (R) |
19 |
22 |
42 |
-78 |
-18 |
4.4835 |
|
Inferior temporal gyrus (R) |
37 |
10 |
63 |
-60 |
-12 |
4.1414 |
|
Inferior occipital gyrus (L) |
19 |
32 |
-30 |
-75 |
-12 |
5.5993 |
|
Calcarine(L) |
18 |
38 |
-9 |
-99 |
18 |
4.8107 |
|
Middle occipital gyrus (R) |
39 |
246 |
45 |
-72 |
39 |
6.425 |
|
Rolandic Operculum(R) |
|
15 |
39 |
-9 |
21 |
4.7932 |
|
Superior frontal gyrus (L) |
10 |
18 |
-21 |
63 |
21 |
4.4066 |
|
Middle occipital gyrus (L) |
19 |
99 |
-27 |
-87 |
36 |
5.7759 |
|
Angular(L) |
39 |
60 |
|
|
|
|
|
Anterior cingulate (L) |
24 |
12 |
-3 |
0 |
30 |
-4.9089 |
MCI<HC |
Cuneus |
7 |
25 |
3 |
-81 |
36 |
5.5245 |
MCI>HC |
Superior frontal gyrus (R) |
6 |
77 |
-18 |
36 |
54 |
6.0966 |
|
Postcentral(L) |
3 |
12 |
-36 |
-24 |
45 |
3.7934 |
|
Postcentral(R) |
3 |
19 |
45 |
-36 |
66 |
4.3482 |
Note: R stands for the Right;L stands for the Left
Seed |
BA |
Cluster Size |
MNI |
Peak intensity |
|||
x |
y |
z |
|||||
Fusiform(L) |
19 |
14 |
-27 |
-81 |
-18 |
4.13 |
MCI>HC |
Inferior occipital gyrus (R) |
19 |
10 |
48 |
-81 |
-15 |
4.3967 |
|
Thalamus |
22 |
-3 |
-18 |
9 |
4.8668 |
||
Caudate(L) |
19 |
-6 |
-3 |
6 |
5.3823 |
||
Middle occipital gyrus (R) |
39 |
98 |
48 |
-72 |
36 |
5.2411 |
|
Thalamus(R) |
48 |
12 |
-21 |
12 |
6.0615 |
||
Caudate(R) |
13 |
21 |
21 |
18 |
15 |
5.415 |
|
Middle occipital gyrus (L) |
19 |
10 |
-30 |
-90 |
27 |
3.9977 |
|
Middle frontal gyrus |
10 |
11 |
36 |
51 |
33 |
4.6613 |
|
Supra Marginal(R) |
40 |
15 |
63 |
-36 |
45 |
4.9647 |
|
Precentral |
6 |
17 |
57 |
9 |
42 |
5.0526 |
|
Postcentral |
3 |
14 |
57 |
-21 |
54 |
4.2439 |
|
Superior parietal (R) |
7 |
35 |
30 |
-63 |
63 |
4.5419 |
|
Middle frontal gyrus (R) |
6 |
16 |
33 |
6 |
66 |
4.6416 |
|
Precentral(R) |
4 |
17 |
30 |
-30 |
72 |
4.8142 |
|
Note: R stands for the Right;L stands for the Left |
Seed |
BA |
Cluster size |
MNI |
Peak intensity |
|||
X |
Y |
Z |
|||||
Thalamus(L) |
10 |
-15 |
-12 |
6 |
-4.8743 |
MCI<HC |
|
Supplementary motor area (R) |
6 |
23 |
6 |
6 |
57 |
-4.3916 |
|
Superior frontal (R) |
8 |
10 |
27 |
36 |
54 |
4.842 |
MCI>HC |
Precentral(R) |
3 |
10 |
24 |
-24 |
78 |
4.2343 |
|
Note: R stands for the Right;L stands for the Left |