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Correlations between cognitive reserve and gray matter volume and cognitive impairment in patients of Alzheimer’s disease
GAO Ziwen, ZHU Wanqiu, LI Xiaoshu, LI Meiqin, ZHOU Shanshan, TIAN Yanghua, WU Xingqi, GENG Zhi, LI Xiaohu, YU Yongqiang
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Correlations between cognitive reserve and gray matter volume and cognitive impairment in patients of Alzheimer’s disease
Objective: Education can be used to reflect cognitive reserve (CR), in this study, we aimed to explore the relationship between education level and changes of brain gray matter volume (GMV) as well as the progression of cognitive impairment in Alzheimer’s disease (AD) patients. Methods: Fifty-seven patients with AD (further divided into mild, moderate and sever groups according to the severity of dementia), 57 patients with amnestic mild cognitive impairment (aMCI) and 52 healthy controls (HC) were collected in this study to obtain high-resolution 3-dimensional T1 structure images. GMV of brain regions related to educational years in AD patients were obtained using VBM8 and SPM8 software, which were then taken as the regions of interest (ROI). The correlation analyses between GMV of ROIs and education were conducted in HC, aMCI, mild, moderate, and severe AD group, separately. AD and aMCI patients were divided into high cognitive reserve (CR+) group and low cognitive reserve (CR-) group according to the median years of education within the entire cognitive impairment sample. The GMV of ROIs were compared in CR+ and CR-groups at each cognitive level. Results: In AD group, the GMV of the left middle cingulate cortex was negatively correlated with the years of education (FDR correction, P< 0.05). Further stratified analysis showed that it was only negatively correlated with the years of education in mild AD group and aMCI group (r=-0.637, P= 0.006 and r =-0.293, P=0.033, respectively). In addition, in mild and moderate AD groups, the GMV of left middle cingulate cortex in CR+ group was significantly lower than that in CR- group (both P< 0.05). Conclusion: AD patients with higher education showed more severe gray matter volume atrophy of the left middle cingulate cortex at a given level of global cognition, reflecting the notion that AD patients with higher reserve can withstand a greater amount of pathology, which confirms the protection effect of cognitive reserve on AD patients.
Alzheimer’s Disease / Amnestic mild cognitive impairment / Cognitive reserve / Magnetic resonance imaging / Voxel-based morphometry {{custom_keyword}} /
表1 基本人口学资料 |
| 指标 | HC (n=52) | aMCI (n=57) | AD(n=57) | P值 |
|---|---|---|---|---|
| 年龄/岁 | 66.38±7.3 | 66.33±7.47 | 67.74±8.28 | 0.55 |
| 性别(男/女) | 20/32 | 26/31 | 22/35 | 0.678 |
| 教育程度/年 | 11.65±3.42 | 9.37±4.77 | 6.14±5.38 | <0.001* |
| MMSE | 28.58±1.18 | 26.35±1.58 | 15.28±5.22 | <0.001* |
| 颅内总体积/mm3 | 1 371.12±102.691 | 1 352.925±99.695 | 1 314.274±109.086 | 0.015* |
| 注：连续变量组间比较采用单因素ANOVA;分类变量组间比较采用卡方检验。*P< 0.05,说明差异有统计学意义。 |
表2 左中扣带灰质体积值分组与教育程度的相关性 |
| 分组 | HC (n=52) | aMCI (n=57) | 轻度AD (n=21) | 中度AD (n=22) | 重度AD (n=14) |
|---|---|---|---|---|---|
| 左中扣带回体积与教育程度的相关性 | r=-0.065 P=0.659 | r=-0.293* P=0.033 | r=-0.637* P=0.006 | r=-0.296 P=0.233 | r=-0.411 P=0.239 |
| 注：*P< 0.05,说明差异有统计学意义。 |
图1 AD患者脑灰质体积与教育程度的相关性注：a~c显示与教育相关的脑区（左侧中扣带回）,FDR校正,P< 0.05; d为左侧中扣带回灰质体积与教育年限相关性分析的散点图。 |
表3 相同认知水平下CR+和CR-组的组间比较 |
| aMCI(n=57) | 轻度AD(n=21) | 中度AD(n=22) | 重度AD(n=14) | |||||
|---|---|---|---|---|---|---|---|---|
| CR-(n=22) | CR+(n=35) | CR-(n=12) | CR+(n=9) | CR-(n=15) | CR+(n=7) | CR-(n=7) | CR+(n=7) | |
| 年龄/年 | 64.79±6.57 | 68.46±8.22 | 66.58±5.66 | 70.22±7.68 | 69.27±7.36 | 62.86±9.33 | 63.71±7.34 | 72.14±12.13 |
| 性别（男/女） | 9/13 | 17/18 | 6/6 | 3/6 | 5/10 | 3/4 | 2/5 | 3/4 |
| MMSE | 26.18±1.65 | 26.58±1.47 | 19.83±3.19 | 20.67±2.12 | †*12（11-14） | 17.43±1.72* | 7.86±5.11 | 10.86±1.46 |
| 颅内总体积/mm3 | 1353.17± 97.12 | 1352.59± 105.25 | 1341.59± 95.19 | 1314.34± 112.45 | 1312.50± 98.90 | 1290.83± 123.87 | 1322.10± 123.65 | 1286.79± 145.08 |
| 左扣带回灰质体积/mm3 | 0.51±0.05 | 0.48±0.06 | 0.51±0.04* | 0.45±0.03* | 0.50±0.04* | 0.44±0.05* | 0.44±0.05 | 0.431±0.04 |
| 注：符合正态分布连续变量数据采用独立双样本t检验,†表示数据不满足正态分布,采用非参数秩和检验;分类变量采用卡方检验及Fisher精确检验。*P< 0.05,差异具有统计学意义。将aMCI与AD纳入认知损害组,并根据痴呆严重程度将AD分为轻、中、重组。依据教育年限中位数将患者分为高认知储备（CR+）组与低认知储备（CR-）组。在MCI、轻、中、重AD各组内,CR+分别与同组内的CR-相比较。 |
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Cognitive reserve (CR) shows protective effects in Alzheimer's disease (AD) and reduces the risk of dementia. Despite the clinical significance of CR, a clinically useful diagnostic biomarker of brain changes underlying CR in AD is not available yet. Our aim was to develop a fully-automated approach applied to fMRI to produce a biomarker associated with CR in subjects at increased risk of AD. We computed resting-state global functional connectivity (GFC), i.e. the average connectivity strength, for each voxel within the cognitive control network, which may sustain CR due to its central role in higher cognitive function. In a training sample including 43 mild cognitive impairment (MCI) subjects and 24 healthy controls (HC), we found that MCI subjects with high CR (> median of years of education, CR+) showed increased frequency of high GFC values compared to MCI-CR- and HC. A summary index capturing such a surplus frequency of high GFC was computed (called GFC reserve (GFC-R) index). GFC-R discriminated MCI-CR+ vs. MCI-CR-, with the area under the ROC = 0.84. Cross-validation in an independently recruited test sample of 23 MCI subjects showed that higher levels of the GFC-R index predicted higher years of education and an alternative questionnaire-based proxy of CR, controlled for memory performance, gray matter of the cognitive control network, white matter hyperintensities, age, and gender. In conclusion, the GFC-R index that captures GFC changes within the cognitive control network provides a biomarker candidate of functional brain changes of CR in patients at increased risk of AD.
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