Background
Glaucoma, one of the leading causes of blindness worldwide, damages the optic nerve and causes visual impairment [
1,
2]. Glaucoma is strongly related to aging [
3] and it is known that individuals with glaucoma are at high risk of brain health problems such as dementia, cognitive impairment, and depression [
4‐
8]. Recent evidence suggests that glaucoma is an inflammatory neurodegenerative disease. Accordingly, aging and environmental stressors can induce mitochondrial dysfunction in retinal ganglion cells, and this process can increase the levels of inflammatory molecules (cytokines and chemokines), and consequently lead to glaucoma [
9].
The effect of glaucoma on brain health has been reported by numerous studies using structural magnetic resonance imaging (MRI), which is useful in detecting neurodegeneration [
10]. Studies have demonstrated that glaucoma patients have smaller visual cortex volumes in the brain (e.g., middle occipital gyrus, superior occipital gyrus, and precentral gyrus) [
11‐
13]. However, only a few studies have investigated the link between glaucoma and changes in brain structures beyond visual cortices by utilizing brain MRI [
14‐
16].
Frezzotti et al. reported that individuals with glaucoma had smaller frontoparietal cortex, hippocampus, and cerebellar cortex volumes compared with age-matched healthy individuals, using voxel-based morphometry [
15].
Wang et al. conducted voxel-based and surface-based morphometry in 36 glaucoma patients and 20 healthy individuals, and found that the glaucoma patients had smaller volumes of the putamen, thalamus, and right hippocampus, as well as reduced cortical thicknesses in some small regions of the frontal, temporal, parietal, and occipital lobes [
16]. Another study also found that glaucoma patients had decreased volumes of various small regions of the frontal, temporal, parietal, and occipital lobes compared with age- and sex-matched healthy individuals based on voxel-based morphometry [
14]. These studies mainly used voxel-based morphometry, which allows the visualization of small brain regions associated with glaucoma, without predefining brain regions. By contrast, the region-of-interest (ROI)-based approach enables an easier clinical interpretation by defining clinically meaningful brain regions a priori. To the best of our knowledge, no study has used the ROI-based approach to investigate the linkage between glaucoma and brain structures beyond the visual cortices. Moreover, cortical thickness is known to be more sensitive to brain structural changes than volumetric measures [
17,
18].
In this study, we aimed to compare ROI-based cortical thickness and subcortical volume on brain MRI between individuals with and without glaucoma. We also compared neuropsychological performance in these groups.
Results
The mean age of both the glaucoma group and the non-glaucoma group was 70 years old. Women accounted for 59.4% of the total population. The percentage of participants with hypertension was significantly higher in the glaucoma group compared to the non-glaucoma group (
P < 0.001). Similarly, the percentage of participants with diabetes mellitus was higher in the glaucoma group than in the non-glaucoma group. The fasting blood glucose level was significantly higher in the participants with glaucoma than in those without glaucoma (
P = 0.008) (Table
1).
Table 1
Demographic and clinical characteristics of the study population
Age (years) | 70.97 ± 5.37 | 70.57 ± 5.32 | 0.63 |
Sex |
Male | 26 (40.6) | 52 (40.6) | 1.00 |
Female | 38 (59.4) | 76 (59.4) | |
Education level |
< middle school | 39 (60.9) | 78 (60.9) | 1.00 |
≥ middle school | 25 (39.1) | 50 (39.1) | |
Marital status |
Married | 51 (79.7) | 97 (76.4) | 0.61 |
Non-married | 13 (20.3) | 30 (23.6) | |
Hypertension |
Yes | 50 (78.1) | 48 (37.5) | < 0.001 |
No | 14 (21.9) | 80 (62.5) | |
Angina or myocardial infarction |
Yes | 9 (14.1) | 15 (11.7) | 0.64 |
No | 55 (85.9) | 113 (88.3) | |
Diabetes mellitus |
Yes | 27 (42.2) | 23 (18.0) | < 0.001 |
No | 37 (57.8) | 105 (82.0) | |
Smoking status |
Current smoker | 3 (4.7) | 3 (2.3) | 0.54 |
Former smoker | 20 (31.3) | 35 (27.3) | |
Never smoker | 41 (64.1) | 90 (70.3) | |
Alcohol consumption |
Yes | 33 (51.6) | 71 (55.9) | 0.57 |
No | 31 (48.4) | 56 (44.1) | |
Body mass index (kg/m2) |
< 18.5 | 0 (0.0) | 1 (0.8) | 0.68 |
18.5-22.9 | 18 (28.1) | 33 (25.8) | |
23.0-24.9 | 21 (32.8) | 35 (27.3) | |
≥ 25.0 | 25 (39.1) | 59 (46.1) | |
Systolic blood pressure (mmHg) |
< 120 | 19 (29.7) | 31 (24.2) | 0.74 |
120-139 | 28 (43.8) | 62 (48.4) | |
140-159 | 15 (23.4) | 28 (21.9) | |
≥ 160 | 2 (3.1) | 7 (5.5) | |
Diastolic blood pressure (mmHg) |
< 80 | 48 (75.0) | 84 (65.6) | 0.23 |
80-90 | 15 (23.4) | 35 (27.3) | |
90-100 | 0 (0.0) | 7 (5.5) | |
≥ 100 | 1 (1.6) | 2 (1.6) | |
Fasting blood glucose (mg/dL), mean (standard deviation) | 109.94 ± 34.23 | 99.34 ± 20.66 | 0.008 |
Total cholesterol (mg/dL), mean (standard deviation) | 186.23 ± 38.56 | 177.90 ± 33.44 | 0.13 |
The mean (standard deviation) cortical thickness of the occipital lobe was 1.88 mm (0.10) in the glaucoma group and 1.92 mm (0.09) in the non-glaucoma group. The glaucoma group had smaller subcortical volumes of the thalamus, caudate, pallidum, amygdala than the non-glaucoma group (Table
2).
Table 2
Differences in cortical thickness and subcortical volume between individuals with glaucoma and their age, sex, and educational level-matched individuals without glaucoma
Cortical thickness (mm) | Global | 2.41 ± 0.09 | 2.43 ± 0.09 | 0.16 |
| Frontal lobe | 2.46 ± 0.11 | 2.48 ± 0.11 | 0.39 |
| Parietal lobe | 2.16 ± 0.12 | 2.20 ± 0.11 | 0.051 |
| Temporal lobe | 2.70 ± 0.11 | 2.72 ± 0.12 | 0.17 |
| Occipital lobe | 1.88 ± 0.10 | 1.92 ± 0.09 | 0.005 |
| Cingulate | 2.45 ± 0.13 | 2.46 ± 0.14 | 0.58 |
| Insula | 2.84 ± 0.13 | 2.84 ± 0.16 | 0.86 |
Subcortical volume (mm3) | Thalamus | 6057.84 ± 644.70 | 6360.02 ± 675.99 | 0.003 |
| Caudate | 3033.387 ± 447.86 | 3222.19 ± 510.70 | 0.013 |
| Putamen | 4123.42 ± 466.39 | 4251.56 ± 531.30 | 0.10 |
| Pallidum | 1729.90 ± 212.57 | 1817.86 ± 202.77 | 0.006 |
| Hippocampus | 3646.42 ± 402.72 | 3757.53 ± 360.48 | 0.054 |
| Amygdala | 1424.78 ± 196.56 | 1500.58 ± 207.17 | 0.016 |
| Nucleus accumbens | 363.53 ± 69.87 | 380.01 ± 78.60 | 0.16 |
The MMSE and SNSB scores were analysed and the glaucoma group had a significantly lower MMSE score than the non-glaucoma group (Table
3). In addition, the glaucoma group had lower average scores in SVLT recall, K-BNT, COWAT phonemic, and Stroop test-color readings compared to the non-glaucoma group.
Table 3
Differences in MMSE and SNSB test scores between individuals with glaucoma and their age, sex, and educational level-matched individuals without glaucoma
MMSE | 24.95 ± 2.93 | 26.01 ± 3.07 | 0.016 |
SNSB |
SVLT recall total score | −0.39 ± 0.98 | −0.31 ± 1.03 | 0.60 |
SVLT delayed recall | − 0.44 ± 1.17 | − 0.46 ± 1.17 | 0.90 |
RCFT delayed recall | − 0.14 ± 0.95 | − 0.33 ± 1.03 | 0.23 |
RCFT copy | −0.35 ± 0.99 | − 0.82 ± 1.38 | 0.018 |
K-BNT | −0.45 ± 1.18 | −0.32 ± 0.99 | 0.41 |
COWAT animal | −0.32 ± 1.09 | −0.32 ± 0.90 | 1.00 |
COWAT phonemic | −0.57 ± 1.02 | −0.46 ± 1.01 | 0.47 |
Stroop Test color reading | −0.73 ± 1.12 | −0.30 ± 1.21 | 0.020 |
K-TMT-E Part B | −0.37 ± 1.70 | −0.45 ± 1.69 | 0.79 |
In the unadjusted model, the glaucoma group had significantly reduced cortical thickness in the occipital lobe and reduced volumes of the thalamus, caudate, putamen, pallidum, hippocampus, and amygdala compared with the non-glaucoma group. In the adjusted model, the reduced occipital thickness in the glaucoma group did not remain significant. The reduced volumes of the subcortical structures remained significant, except for the putamen and nucleus accumbens (Table
4).
Table 4
Cortical thickness and subcortical volume in individuals with glaucoma compared to age, sex, and educational level-matched individuals without glaucoma
Cortical thickness (mm) | Global | −0.020 | 0.012 | 0.20 | −0.011 | 0.014 | 0.75 |
| Frontal lobe | −0.015 | 0.015 | 0.46 | −0.007 | 0.018 | 0.94 |
| Parietal lobe | −0.035 | 0.015 | 0.070 | −0.021 | 0.017 | 0.67 |
| Temporal lobe | −0.024 | 0.015 | 0.20 | −0.016 | 0.018 | 0.67 |
| Occipital lobe | −0.040 | 0.013 | 0.014 | −0.016 | 0.015 | 0.67 |
| Cingulate | −0.011 | 0.018 | 0.62 | −0.003 | 0.022 | 0.94 |
| Insula | 0.004 | 0.021 | 0.86 | 0.002 | 0.024 | 0.94 |
Subcortical volume (mm3) | Thalamus | −300.45 | 73.97 | 0.004 | −212.81 | 88.03 | 0.028 |
| Caudate | −187.61 | 63.20 | 0.007 | −170.03 | 73.73 | 0.029 |
| Putamen | − 126.91 | 63.99 | 0.055 | −151.41 | 75.03 | 0.051 |
| Pallidum | −87.45 | 26.36 | 0.004 | −103.59 | 31.26 | 0.007 |
| Hippocampus | −110.42 | 47.58 | 0.028 | −141.37 | 55.94 | 0.026 |
| Amygdala | −75.44 | 26.58 | 0.009 | −87.94 | 31.42 | 0.018 |
| Nucleus accumbens | −16.32 | 10.17 | 0.11 | −20.44 | 11.60 | 0.078 |
MMSE scores were lower in the glaucoma group than in the non-glaucoma group, but this difference showed borderline significance (
P = 0.057) (Table
5). Scores for the total SVLT recall, K-BNT, COWAT phonemic, Stroop test-color reading, and K-TMT-E Part B tests were lower in the glaucoma group than in the non-glaucoma group, but only the Stroop test-color reading exhibited statistical significance (
P = 0.04).
Table 5
MMSE and SNSB test scores in the glaucoma group compared to age, sex, and educational level-matched non-glaucoma group
MMSE | −1.13 | 0.45 | 0.013 | − 1.02 | 0.54 | 0.057 |
SNSB |
SVLT recall total score | −0.074 | 0.15 | 0.62 | −0.041 | 0.17 | 0.81 |
SVLT delayed recall | 0.031 | 0.17 | 0.86 | 0.013 | 0.21 | 0.95 |
RCFT delayed recall | 0.19 | 0.15 | 0.22 | 0.23 | 0.18 | 0.20 |
RCFT copy | 0.47 | 0.20 | 0.017 | 0.48 | 0.23 | 0.039 |
K-BNT | −0.14 | 0.16 | 0.38 | −0.050 | 0.19 | 0.79 |
COWAT animal | 0.001 | 0.15 | 1.00 | 0.021 | 0.18 | 0.91 |
COWAT phonemic | −0.11 | 0.15 | 0.47 | −0.14 | 0.18 | 0.45 |
Stroop Test color reading | −0.43 | 0.18 | 0.019 | −0.44 | 0.21 | 0.038 |
K-TMT-E Part B | 0.081 | 0.26 | 0.76 | −0.067 | 0.29 | 0.82 |
After correcting for multiple comparisons using the Bonferroni-Holm method, only the associations with volumes of the pallidum and amygdala remained significant in the adjusted model (Supplementary Table
1). None of the differences in the associations of glaucoma with cortical thickness and subcortical volume between individuals with and without hypertension was statistically significant (Supplementary Table
2). None of the differences in the associations of glaucoma with cortical thickness and subcortical volume between individuals with and without diabetes mellitus was statistically significant, except insula (Supplementary Table
3).
Discussion
This study investigated differences in the cortical thickness and subcortical volumes of the brain between the glaucoma group and their age, sex, and educational level-matched non-glaucoma group. We found that subcortical volumes of the thalamus, caudate, putamen, pallidum, hippocampus, and amygdala were significantly smaller in the glaucoma group when compared with the non-glaucoma group. This remained significant after adjusting for potential confounding variables. Although borderline insignificance was observed in the fully adjusted model, the MMSE score was significantly lower in individuals with glaucoma when compared with those without glaucoma. In addition, the Stroop test-color reading score was significantly lower in the individuals with glaucoma.
In this study, we observed that the volume of the brain regions associated with the cerebral limbic system was thinner in individuals with glaucoma compared with individuals without glaucoma. This finding is consistent with previous studies showing a decrease in hippocampus volume in individuals with glaucoma compared with individuals without glaucoma [
15,
16]. A study with a small sample size (
n = 25) also demonstrated that the hippocampus volume was smaller in individuals with glaucoma than in individuals without glaucoma, but the difference was not statistically significant [
25]. Other studies have reported that the worsening of open-angle glaucoma was related to the atrophy of the hippocampus [
26]. In addition to hippocampus atrophy, the volume of the amygdala was significantly reduced in individuals with glaucoma in our study, consistent with a previous report [
25]. Given that the hippocampus and amygdala are responsible for memory and emotion [
27,
28], the reduced volumes of the hippocampus and amygdala in individuals with glaucoma could lead to memory impairment and mood disorders. This notion is in line with epidemiological studies showing that individuals with glaucoma are at a higher risk for Alzheimer’s disease [
29,
30] and depression [
31‐
33]. Additionally, volumes of the basal ganglia (thalamus, caudate, putamen, and pallidum) were reduced in individuals with glaucoma compared to those without glaucoma in our study. This is consistent with previous studies demonstrating smaller volumes of the thalamus [
16] and the caudate [
34] in individuals with glaucoma compared to those without glaucoma.
In our study, individuals with glaucoma had a significantly reduced occipital thickness, but this reduction did not remain significant after adjusting for covariates, including hypertension and diabetes mellitus. Previous studies have shown mixed results regarding the association between glaucoma and the occipital lobe thickness. Some studies have reported smaller occipital lobe volumes in individuals with primary open-angle glaucoma compared with those without glaucoma [
14,
15,
34] whereas another study showed a greater occipital lobe volume in glaucoma patients [
35]. Future studies are required to investigate the association between glaucoma and the occipital lobe.
There are biological mechanisms that may explain the linkage between glaucoma and brain volume reduction (or neurodegeneration). One of the mechanisms is that glaucoma and neurodegenerative diseases (mainly Alzheimer’s disease) share common pathological features. The development of Alzheimer’s disease is caused by abnormal protein (amyloid beta and hyperphosphorylated tau) accumulation in the brain. An eye tissue analysis in mice with glaucoma demonstrated that an increase in amyloid beta protein was significantly associated with apoptosis of retinal nerve cells [
36]. Another study found that tau transgenic (knockout) mice had hyperphosphorylated tau proteins in the nerve fibre layer of retinal ganglion cells [
37]. An alternative mechanism is neuroinflammation in retinal ganglion cells. Internal and external stressors can induce mitochondrial dysfunction in retinal ganglion cells via increased oxidative stress and activation of inflammatory processes (e.g., proinflammatory cytokine and chemokine production, blood-retinal barrier damage, T-cell migration and activation [
9]). In order to better understand the mechanism that underlies the association between glaucoma and brain structures, it would be desirable to relate morphological and functional abnormalities in glaucoma patients to brain structural changes. Future studies may need to assess the burden of amyloid beta and tau protein as well as the level of inflammatory markers in glaucoma patients and investigate whether these changes affect brain cortical thickness and subcortical volume.
This study has several limitations. First, because of the cross-sectional nature, it is not possible to infer a temporal relationship between glaucoma and the brain volume reduction. Future studies are needed to investigate the temporal relationship by following brain MRI markers. Second, there is a possibility of unmeasured confounding variables. For example, our data did not collect information on the type or duration of glaucoma in the participants. However, there is a paucity of evidence suggesting differences in brain MRI markers between the different types of glaucoma. Only one study has reported a decreased occipital lobe volume in individuals with high tension glaucoma versus normal tension glaucoma [
38]. Similarly, given that glaucoma can occur secondary to diabetes mellitus [
39,
40], subcortical volume reductions that we found to be associated with glaucoma in this study could also be attributed to diabetes mellitus. To attempt to address this limitation related to glaucoma secondary to diabetes, we additionally conducted the analyses stratified by history of diabetes and hypertension. Differences in the associations of glaucoma with cortical thickness and subcortical volume between individuals with and without history of hypertension were not statistically significant (Supplementary Table
2). Differences in the associations of glaucoma with cortical thickness and subcortical volume between individuals with and without history of diabetes were not statistically significant, except insula (Supplementary Table
3).
Conclusions
In conclusion, our study showed that individuals with glaucoma had smaller volumes of the thalamus, caudate, putamen, pallidum, amygdala, and hippocampus compared with their age-, sex-, and education level-matched individuals without glaucoma, after adjusting for potential confounders. These findings add to the existing literature on the association between glaucoma and brain structures, beyond the visual cortices. Large-scale prospective studies are needed to further confirm this association.
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