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Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study
Clinical Radiology xxx (2016) e1ee7
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Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study Z.-L. Wang a, d, L. Zou b, Z.-W. Lu c, X.-Q. Xie a, Z.-Z. Jia d, C.-J. Pan d, G.-X. Zhang a, *, X.-M. Ge d, ** a
Department of Radiology, Shanghai General Hospital of Nanjing Medical University, NO.100 Haining Road, Shanghai 200080, China b Department of Radiology, Changzhou Second People’s Hospital, Nanjing Medical University, No.29 Xinglong Road, Changzhou 213003, China c Information Science and Egineering College, Changzhou University, No.1 Gehu Road, Changzhou 213164, China d Department of Radiology, The First Affiliated Hospital of Soochow University, No.188, Shizi Road, Suzhou 215006, China
art icl e i nformat ion Article history: Received 8 August 2016 Received in revised form 11 October 2016 Accepted 21 November 2016
AIM: To explore the altered spontaneous cerebral activity patterns and impaired functional regions in patients with diabetic retinopathy (DR) using resting-state functional magnetic resonance imaging (rs-fMRI) based on the amplitude of low-frequency fluctuations (ALFF) algorithm. MATERIALS AND METHODS: Twenty-one patients with DR (mean age, 54.99.9 years; 11 females) and 17 healthy control subjects (54.85.7 years; 9 females) were prospectively studied. The DR patients underwent laboratory tests. All individuals underwent a neuropsychological test. The differences in the ALFF values between the two groups were compared. The relationships between ALFF values and clinical measurements were analysed using a multiple-factor analysis. RESULTS: Compared to the controls, the DR group showed significantly increased ALFF values in the bilateral occipital gyrus, right lingual gyrus, and precuneus, and decreased values in the right posterior/anterior cerebellar lobe and the parahippocampal, fusiform, superior temporal, inferior parietal, and angular gyrus. Furthermore, the Montreal Cognitive Assessment (MoCA) scores were negatively correlated with decreased ALFF values in the right occipital lobe of the DR group, while increased ALFF values in the right precuneus and lingual gyrus were found to be positively correlated with glycosylated haemoglobin (HbA1c) levels. CONCLUSIONS: Patients with DR showed spontaneous cerebral activity abnormalities in many cerebral regions that were associated with cognitive impairments. HbA1c levels altered spontaneous cerebral activity in DR patients. Ó 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
* Guarantor and correspondent: G.-X. Zhang, Department of Radiology, Shanghai General Hospital of Nanjing Medical University, 100, Haining Road, Shanghai, China. Tel.: þ86 13386259611. ** Guarantor and correspondent: X.-M. Ge. E-mail address: [email protected] (X.-M. Zhang).
Introduction Type II diabetes mellitus (T2DM) affects approximately 240 million people worldwide and can lead to long-term
http://dx.doi.org/10.1016/j.crad.2016.11.012 0009-9260/Ó 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
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complications affecting the brain, nerves, eyes, kidneys, and blood vessels.1,2 Brain damage is a major complication of T2DM and can lead to cognitive dysfunction; however, the pathophysiological mechanism of cerebral injury is not clear. Several factors that lead to neuropathy may cause cerebral damage in T2DM patients, including increased oxidative stress, chronic hyperglycaemia, vascular impairments, and metabolic dysregulation.1,3e5 Ryan et al.6 reported that diabetic retinopathy (DR) is associated with decreased cognitive performance in diabetic patients.6 DR is a common cause of adult visual impairment and affects the retinal vasculature. Evidence exists that supports the association of retinopathy with visual cortex impairment and cognitive dysfunction or dementia.7e11 Functional magnetic resonance imaging (fMRI) has been widely utilised to evaluate cerebral function. On fMRI, the amplitude of low-frequency fluctuations (ALFF) algorithm reflects spontaneous regional neural activity.12,13 This method quantifies the total power over given time courses within a specific frequency band of 0.01e0.1 Hz, which is considered physiologically important.7,9,13 Recent studies have shown that cerebral neural oscillations cover a wide frequency band, including slow-3 (0.073e0.198 Hz), slow-4 (0.027e0.073 Hz), and slow-5 (0.01e0.027 Hz). Furthermore, studies have demonstrated that the ALFF in the slow5 band is lower than that in the slow-4 band in several regions of the cerebrum, such as the precuneus, thalamus, and basal ganglia.10 The Montreal Cognitive Assessment (MoCA) and the Mini Mental State Examination (MMSE) are used by physicians to assess cognitive impairment in patients. A previous study showed that the sensitivity (90%) and specificity (87%) of the MoCA were excellent when assessing mild cognitive damage. ALFF values in the bilateral occipital and cerebellum were negatively correlated with MoCA scores. In previous studies, the ALFF algorithm has been used to map differences between healthy controls and T2DM patients7,14; however, to the authors’ knowledge, resting state (rs-ALFF) values have not been used in DR patients to evaluate alterations in brain functional regions. In the present study, it was hypothesised that DR patients show abnormal ALFF during spontaneous cerebral activity and that cognitive performance is associated with specific frequency bands in these cerebral regions. This study aimed to evaluate the spontaneous cerebral activity patterns in DR patients using rs-fMRI with an ALFF algorithm.
characteristics of the proliferative DR group were preretinal haemorrhage, vitreous haemorrhage, and neovascularisation in the fundus on examination. The characteristics of the non-proliferative DR group were microaneurysms, hara exudates, and retinal haemorrhages. Sixteen sex-, age-, and education-matched patients without T2DM (mean age 54.85.7 years) were enrolled in the healthy control group, including nine women and seven men. The exclusion criteria were as follows: patients with other eye diseases, including active uveitis, glaucoma, and cornea and/or lens pathology, or patients with contraindications for MRI examination. The visual acuity and intraocular pressure of the patients were assessed using Snellen’s chart and applanation tonometry.11 After pupil dilatation, examination of the fundus was performed for each patient. The haemoglobin A1c (HbA1c) levels and the duration were recorded in both groups. The HbA1c levels were measured using highperformance liquid chromatography (HA-8140; Menarini Diagnostics, Florence, Italy).11
Neuropsychological testing To assess patient cognitive function and neuropsychological status, the MoCA and MMSE cognitive tests were performed on all participants within 1 hour after MRI. The MMSE assesses five cognitive domains, i.e., attention, recall, registration, orientation, calculation, and language. The MoCA assesses seven other cognitive domains2,7 including executive function. The results of the cognitive function tests in both groups are shown in Table 1.
MRI techniques MRI was performed using a 3 T system (Philips, Gyroscan Intera Master, Best, The Netherlands). While the images were being acquired, all participants were advised to close their eyes, relax their mind, and keep their head still. Functional data were generated using gradient-recalled echo-planar imaging sequencing. The following parameters were used: 2363 ms repetition time, 61 ms echo time, 90 flip angle, 4 mm slice thickness, 1 mm gap, 2323 cm field of view, and 128128 matrix. Conventional T1weighted (TR¼250 ms; TE¼50 ms) and T2-weighted (TR¼2480 ms; TE¼136 ms) images were also obtained for traditional image reading.
Data preprocessing
Materials and methods Study sample This study was approved by the participating local institutional review boards and performed according to the ethical standards set forth in 1964 in the Declaration of Helsinki. Both DR and healthy control patients were evaluated. A total of 21 patients (mean age 54.99.9 years) were enrolled in the DR group (proliferative and nonproliferative DR), including 11 women and 10 men. The
Data preprocessing was performed using the Data Processing Assistant for Resting-State Functional MR imaging (DPARSF; http://rfmri.org/DPARSF), which is based on the SPM8 software package (http://www.fil.ion.ucl.ac.uk), and the Resting-State fMRI Data Analysis Toolkit (REST). Two patients were excluded from the analysis because they had more than 2 mm of displacement or 2 of rotation in any direction. Linear regression was applied to remove other false variables, including the signal from the cerebral spinal fluid (CSF) and a region centred in the white matter (WM) of the brain. Individual T1-weighted structural imaging was
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
Z.-L. Wang et al. / Clinical Radiology xxx (2016) e1ee7 Table 1 Demographic and clinical features of the study participants. Characteristics
DR group (n¼21)
p-Value Control group t/x2 values (n¼16)
Age (years old) Gender (F/M) Duration of disease (years) Fasting glucose (mmol/l) HbA1c (%) HOMA-IR Diabetic nephropathy MMSE MoCA
54.99.9 11/10 9.485.01 8.611.54 8.431.71 3.371.08 4/21 28.161.09 21.690.70
54.85.7 9/7 5.68 0.98 5.62 0.94 2.340.97 28.990.71 25.181.88
0.04 0.06 2.46 3.92 8.50 -1.73 -13.42
0.970 0.815 0.019 < 0.001 < 0.001 0.093 < 0.001
*Data are presented as the mean SD. DR, diabetic retinopathy; HbA1c, haemoglobin A1c; HOMA-IR, homeostasis model assessment method-insulin resistance; MMSE, Mini Mental State Examinaton; MoCA, Montreal Cognitive Assessment.
co-registered to the mean of the realigned echo planar imaging images. The other steps included the removal of the first 10 time points from each patient’s data, section timing correction, and spatial normalisation to the Montreal Neurological Institute (MNI) space. Finally, the linear tendency of the time courses was smoothed using an algorithm based on an 8-mm full-width half maximum Gaussian kernel.
Data calculation
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and MoCA and MMSE scores, Pearson correlation analysis was performed using statistical software (SPM8, The FIL Methods Group, Shanghai, China). The threshold p-value for a statistically significant difference was <0.05, and the simulation software was used for correction. All statistical analyses were performed using SPSS version 19.0 (SPSS, Chicago, IL, USA).
Results Clinical demographic characteristics and neuropsychological data A total of 37 patients (20 women, 17 men) were included. The participant demographics of the DR and healthy control groups are listed in Table 1. The HbA1c levels and fasting glucose levels for the DR group were significantly increased compared to the healthy group (DR group versus healthy group; p<0.05). No difference in the MMSE scores was observed between the DR and healthy control groups. Compared to the healthy group, the MoCA scores of the DR group were significantly higher (p<0.01).
Group differences in the ALFF maps
The data calculation scheme was previously reported.8,15 A fast Fourier transform (FFT) was used to transform the time course into frequency. The square root of the power spectrum was computed and then averaged across 0.01e0.08 Hz at each voxel. This averaged square root was considered an ALFF measurement. For each voxel, raw ALFF values were divided by the global brain mean ALFF value for standardisation. Relative to the average ALFF values, standardised ALFFs for each voxel represented the degree of the raw value.
In the DR group, the ALFF values in the superior temporal gyrus, parietal lobe, bilateral occipital lobes, and inferior frontal gyrus were significantly higher than the global average ALFF values (Fig 1). The group differences are shown in Table 2. Increased ALFF values were seen the inferior/middle/bilateral superior occipital gyrus, right lingual gyrus, and precuneus in DR patients compared to the control group (p<0.01). The ALFF values were significantly lower in the DR group in the right posterior/anterior lobe of the cerebellum and the right fusiform, left parahippocampal, right superior temporal, right inferior parietal, and angular gyrus (p<0.01).
Statistical analysis
Correlation between ALFF values and clinical data
The normality of the quantitative variables was analysed using the ShapiroeWalk test. For normally distributed data, clinical differences between the patient and control group were evaluated using a t-test. For non-normal distributions of data or proportions, differences were analysed using the Wilcoxon signed-rank test or x2-test, respectively. A value of p<0.05 was regarded as significant. Differences in age, HbA1c levels, and MMSE scores between the patient and control groups were assessed by a two-sample t-test. A one-sample t-test was performed using the REST (resting-state) statistical analysis. The mean ALFF differences between the DR and healthy groups were assessed by a two-sample t-test. Simulation software (AlphaSim; National Institutes of Health, Bethesda, MD, USA) was used to correct these results, in which p<0.01 was considered significant after Bonferroni correction.7 To study the relationship between the ALFF values in the two groups (DR and healthy control groups) and the fasting plasma glucose levels, duration of disease, HbA1c levels,
The mean ALFF values in the right lingual gyrus and occipital lobe were negatively correlated with the MoCA scores in the DR group (p<0.01, simulation software corrected; Fig 2). A significant positive correlation was observed between the HbA1c levels and ALFF values in the right lingual and right precuneus gyrus (p<0.01, simulation software corrected; Fig 3). None of the regional ALFF values were significantly correlated with disease duration, fasting glucose levels, HOMA-IR (homeostasis model assessment method-insulin resistance), or the number connection test MMSE scores of patients in the DR group (all p<0.05, simulation software corrected).
Discussion In the present study, ALFF values were quantified to investigate spontaneous cerebral activity impairment in patients with DR. Significantly decreased ALFF values were observed in the DR group in their right posterior/anterior
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
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Figure 1 The red colour represents a higher ALFF value in patients with DR than in control subjects, whereas the blue colour represents a lower ALFF value.
Table 2 Cerebral regions showing amplitude of low-frequency fluctuations (ALFF) algorithm value differences between diabetics retinopathy (DR) patients and healthy controls. Brain region
Brodmann area
MNI coordinates x, y, z
Voxels
Mean ALFF value DR versus non-DR
t-Value
p-Value
R posterior lobe of cerebellum R anterior lobe of cerebellum L parahippocampal gyrus R fusiform/ superior temporal gyrus R inferior parietal/angular gyrus R/L superior/middle/ inferior occipital gyrus/R lingual gyrus Precuneus
d 38, 35 22, 37
21, 69, 60 18, 27, 18 48, 24, 54
1566 443 228
0.980.19 versus 1.140.18 1.130.19 versus 1.320.18 0.970.19 versus 1.100.17
2.59 3.89 2.36
0.014 < 0.001 0.024
39, 40 17, 18, 19
45, 42, 52 6, 96, 0
104 1055
1.030.23 versus 1.220.20 1.050.39 versus 0.900.16
2.31 3.08
0.026 0.004
7
18, 63, 39
162
1.150.16 versus 0.990.19
2.90
0.006
MNI, Montreal Neurological Institute; R, right; L, left.
cerebellar lobe and left parahippocampal, right fusiform, superior temporal, inferior parietal, and angular gyrus compared to the healthy control group. Increased ALFF values were observed in the DR group in the bilateral occipital lobe, right lingual gyrus, and precuneus. These results showed an association between clinical and neuropsychological parameters. The present findings provide novel evidence of an abnormal resting state during
spontaneous brain activity in DR patients. These findings might contribute to a further understanding of DR and brain functional alterations. Previous studies have shown abnormalities in spontaneous cerebral activity in functional areas in patients with T2DM7,9,16; however, ALFF data for brain injury in T2DM patients with retinopathy has not been reported yet. In the present study, DR was associated with regions of functional
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
Z.-L. Wang et al. / Clinical Radiology xxx (2016) e1ee7
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Figure 2 ALFF maps showing the correlation between ALFF values and MoCA scores in DR patients (p<0.01, corrected). MoCA scores in DR patients were negatively correlated with ALFF values in the right occipital lobe.
brain impairment, especially in the visual cortex, and impaired cognitive performance. The present results demonstrate that increased brain activity occurs not only in the bilateral occipital lobe of DR patients, but also in the right lingual gyrus and precuneus, which are associated with spontaneous brain activity in the visual centre. Liu et al.17 reported that abnormalities in spontaneous neural activity in primary open angle glaucoma (POAG) patients could be found in the visual cortex, and the decreased activity in the visual regions might be linked to abnormities in visual stimuli processing. An absence of stimulation in the visual centre of patients with DR may result in cortical structure modifications. Previous studies have indicated that developmental visual disorders affect the occipital cortex, e.g., albinism and amblyopia.18,19 Kitajima et al.20 showed a wider calcarine sulcus in patients with a variety of DR conditions using MRI, which suggested a possible link between cortical degeneration and visual field defects. Decreased stimulation of the visual centre may contribute to increased sensitivity in the area of the visual cortex. According to these results, increased ALFF values in the visual cortex may be due to the long-term decreases in the stimulation of the visual centre. Cui et al.7 reported decreased spontaneous visual activity in T2DM patients without retinopathy in a resting state compared to healthy
controls. Most of the patients in their study did not have any clinical visual or sensory alterations. Conversely, in accordance with the present study,14 it has been reported that increased brain activity in regions of T2DM patients is shown mainly in the visual centres, such as the cuneus, bilateral occipital lobes, fusiform gyrus, and precuneus. Cerebral functional area alterations in the visual cortex have been consistently observed in magnetic resonance spectroscopy (MRS) studies10,11 and in a diffusion-weighted imaging study.21 The relationship between retinopathy and brain impairment was well demonstrated in a previous study.11 The compensatory mechanism may temporarily ‘‘cover’’ damage in the functional areas before serious vision loss or blindness occurs. This might explain why a decrease in spontaneous brain activity in the visual areas of DR patients was not observed. Decreased voxels of grey matter density were observed in the right occipital lobe in patients with DR compared to the healthy controls.22 Therefore, the increased ALFF values in the superior/middle/inferior occipital gyrus may be related to a reduction in the grey matter density in patients with DR. The mechanism of the association between increased ALFF values in the occipital gyrus and DR was not clear. Hyperglycaemia may be an important mediator and may play an important role in brain functional impairment in DR patients. Hyperglycaemia
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
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Figure 3 ALFF maps showing the correlation between ALFF values and HbA1c levels in DR patients (p<0.01, corrected). HbA1c levels in the DR group were positively correlated with ALFF values in the precuneus and lingual gyrus.
leads to accelerated accumulation of glycosylation end products and potentially toxic glucose metabolites, which damage retinal microvessels by activating various interconnecting biochemical pathways.23 Retinopathy is generally considered a consequence of hyperglycaemia exposure.24 Apart from the increased ALFF values in the occipital cortex, increased activity was observed in the right lingual gyrus and the precuneus of DR patients in the present study. Previous studies have indicated that the precuneus plays an important role in the neural substrate of visual imagery, and it is primarily responsible for highly integrated tasks, including maintaining wakefulness and regulating visual spatial episodic memory.25,26 According to these findings, a potential relationship was proposed between abnormalities in visual processing areas and DR. Another important finding was the presence of reduced ALFF values in the anterior cerebellar lobe and posterior lobe of DR patients in this study. It has been reported that the cerebellum is associated with cognitive and executive functions.14,27 Studies have shown the distribution of various cognitive regions in the posterior lobe of the cerebellum and of motor functions in the anterior lobe.28 In a recent animal study, degenerative changes were also detected in the cerebellum of streptozotocin-treated
animals in an induced diabetic rat model, e.g., fragmentation of neurofilaments, disarrangement of myelin sheaths, and oligodendrocyte abnormalities.29 Therefore, the present results suggest that reduced spontaneous brain activity in the lobes of the cerebellum is associated with DR-related cognitive dysfunction. Decreased ALFF values were found in the left parahippocampal, right fusiform, superior temporal, inferior parietal, and angular gyrus. These findings were similar to the results of previous studies.17,30,31 These areas play important roles in cognitive function. The present results showed decreased activity in these regions, suggesting an impairment of cognitive function in DR patients. A recent study showed that neuronal necrosis, neuronal cell death, and gliosis contribute to increased ADC values in the brain functional regions of T2MD patients, suggesting that increased spontaneous brain activities are associated with neuronal necrosis and neuronal cell death.32 Abnormalities of the right occipital lobe and lingual gyrus were related to impaired cognitive performance on the MoCA in DR patients. The occipital lobe and lingual gyrus play a role in visual memory, attention, and other visual and cognitive functions.33 Nevertheless, in the present study, the brain functional area that negatively correlated with MoCA score in DR patients is influenced by many factors, such as high
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
Z.-L. Wang et al. / Clinical Radiology xxx (2016) e1ee7
blood sugar, HbA1c. Generally, the present results indicated that a stronger compensation results in greater damage to cognitive function. Furthermore, HbA1c levels were positively associated with ALFF values in the precuneus and lingual gyrus. Retinopathy is generally considered a consequence of exposure to hyperglycaemia. HbA1c values are used to monitor glycaemic control. The results of previous studies have shown a correlation between neuronal loss or dysfunction in the frontal cortex and parietal white matter and HbA1c levels.21,34 Therefore, the present results suggested that HbA1c levels influence cerebral function in DR patients. The present study had several limitations. First, the study sample was relatively small, which limits the generalisation of the study conclusions. Second, the spontaneous cerebral activity patterns in DR patients and healthy controls were analysed. Further studies should include T2MD without and with DR patients. Third, this was a cross-sectional study. It is important to investigate longitudinal changes in the visual region of DR patients. In summary, in the present study, widespread abnormalities of spontaneous resting state cerebral activity were demonstrated in the visual cortex of DR patients. The results demonstrated a significant correlation between neuropsychological impairment and clinical markers.
Acknowledgments This work was financially supported by the National Nature Science Foundation of China (grant nos. 81271384 and 81371623).
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Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
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Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study Z.-L. Wang a, d, L. Zou b, Z.-W. Lu c, X.-Q. Xie a, Z.-Z. Jia d, C.-J. Pan d, G.-X. Zhang a, *, X.-M. Ge d, ** a
Department of Radiology, Shanghai General Hospital of Nanjing Medical University, NO.100 Haining Road, Shanghai 200080, China b Department of Radiology, Changzhou Second People’s Hospital, Nanjing Medical University, No.29 Xinglong Road, Changzhou 213003, China c Information Science and Egineering College, Changzhou University, No.1 Gehu Road, Changzhou 213164, China d Department of Radiology, The First Affiliated Hospital of Soochow University, No.188, Shizi Road, Suzhou 215006, China
art icl e i nformat ion Article history: Received 8 August 2016 Received in revised form 11 October 2016 Accepted 21 November 2016
AIM: To explore the altered spontaneous cerebral activity patterns and impaired functional regions in patients with diabetic retinopathy (DR) using resting-state functional magnetic resonance imaging (rs-fMRI) based on the amplitude of low-frequency fluctuations (ALFF) algorithm. MATERIALS AND METHODS: Twenty-one patients with DR (mean age, 54.99.9 years; 11 females) and 17 healthy control subjects (54.85.7 years; 9 females) were prospectively studied. The DR patients underwent laboratory tests. All individuals underwent a neuropsychological test. The differences in the ALFF values between the two groups were compared. The relationships between ALFF values and clinical measurements were analysed using a multiple-factor analysis. RESULTS: Compared to the controls, the DR group showed significantly increased ALFF values in the bilateral occipital gyrus, right lingual gyrus, and precuneus, and decreased values in the right posterior/anterior cerebellar lobe and the parahippocampal, fusiform, superior temporal, inferior parietal, and angular gyrus. Furthermore, the Montreal Cognitive Assessment (MoCA) scores were negatively correlated with decreased ALFF values in the right occipital lobe of the DR group, while increased ALFF values in the right precuneus and lingual gyrus were found to be positively correlated with glycosylated haemoglobin (HbA1c) levels. CONCLUSIONS: Patients with DR showed spontaneous cerebral activity abnormalities in many cerebral regions that were associated with cognitive impairments. HbA1c levels altered spontaneous cerebral activity in DR patients. Ó 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
* Guarantor and correspondent: G.-X. Zhang, Department of Radiology, Shanghai General Hospital of Nanjing Medical University, 100, Haining Road, Shanghai, China. Tel.: þ86 13386259611. ** Guarantor and correspondent: X.-M. Ge. E-mail address: [email protected] (X.-M. Zhang).
Introduction Type II diabetes mellitus (T2DM) affects approximately 240 million people worldwide and can lead to long-term
http://dx.doi.org/10.1016/j.crad.2016.11.012 0009-9260/Ó 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
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complications affecting the brain, nerves, eyes, kidneys, and blood vessels.1,2 Brain damage is a major complication of T2DM and can lead to cognitive dysfunction; however, the pathophysiological mechanism of cerebral injury is not clear. Several factors that lead to neuropathy may cause cerebral damage in T2DM patients, including increased oxidative stress, chronic hyperglycaemia, vascular impairments, and metabolic dysregulation.1,3e5 Ryan et al.6 reported that diabetic retinopathy (DR) is associated with decreased cognitive performance in diabetic patients.6 DR is a common cause of adult visual impairment and affects the retinal vasculature. Evidence exists that supports the association of retinopathy with visual cortex impairment and cognitive dysfunction or dementia.7e11 Functional magnetic resonance imaging (fMRI) has been widely utilised to evaluate cerebral function. On fMRI, the amplitude of low-frequency fluctuations (ALFF) algorithm reflects spontaneous regional neural activity.12,13 This method quantifies the total power over given time courses within a specific frequency band of 0.01e0.1 Hz, which is considered physiologically important.7,9,13 Recent studies have shown that cerebral neural oscillations cover a wide frequency band, including slow-3 (0.073e0.198 Hz), slow-4 (0.027e0.073 Hz), and slow-5 (0.01e0.027 Hz). Furthermore, studies have demonstrated that the ALFF in the slow5 band is lower than that in the slow-4 band in several regions of the cerebrum, such as the precuneus, thalamus, and basal ganglia.10 The Montreal Cognitive Assessment (MoCA) and the Mini Mental State Examination (MMSE) are used by physicians to assess cognitive impairment in patients. A previous study showed that the sensitivity (90%) and specificity (87%) of the MoCA were excellent when assessing mild cognitive damage. ALFF values in the bilateral occipital and cerebellum were negatively correlated with MoCA scores. In previous studies, the ALFF algorithm has been used to map differences between healthy controls and T2DM patients7,14; however, to the authors’ knowledge, resting state (rs-ALFF) values have not been used in DR patients to evaluate alterations in brain functional regions. In the present study, it was hypothesised that DR patients show abnormal ALFF during spontaneous cerebral activity and that cognitive performance is associated with specific frequency bands in these cerebral regions. This study aimed to evaluate the spontaneous cerebral activity patterns in DR patients using rs-fMRI with an ALFF algorithm.
characteristics of the proliferative DR group were preretinal haemorrhage, vitreous haemorrhage, and neovascularisation in the fundus on examination. The characteristics of the non-proliferative DR group were microaneurysms, hara exudates, and retinal haemorrhages. Sixteen sex-, age-, and education-matched patients without T2DM (mean age 54.85.7 years) were enrolled in the healthy control group, including nine women and seven men. The exclusion criteria were as follows: patients with other eye diseases, including active uveitis, glaucoma, and cornea and/or lens pathology, or patients with contraindications for MRI examination. The visual acuity and intraocular pressure of the patients were assessed using Snellen’s chart and applanation tonometry.11 After pupil dilatation, examination of the fundus was performed for each patient. The haemoglobin A1c (HbA1c) levels and the duration were recorded in both groups. The HbA1c levels were measured using highperformance liquid chromatography (HA-8140; Menarini Diagnostics, Florence, Italy).11
Neuropsychological testing To assess patient cognitive function and neuropsychological status, the MoCA and MMSE cognitive tests were performed on all participants within 1 hour after MRI. The MMSE assesses five cognitive domains, i.e., attention, recall, registration, orientation, calculation, and language. The MoCA assesses seven other cognitive domains2,7 including executive function. The results of the cognitive function tests in both groups are shown in Table 1.
MRI techniques MRI was performed using a 3 T system (Philips, Gyroscan Intera Master, Best, The Netherlands). While the images were being acquired, all participants were advised to close their eyes, relax their mind, and keep their head still. Functional data were generated using gradient-recalled echo-planar imaging sequencing. The following parameters were used: 2363 ms repetition time, 61 ms echo time, 90 flip angle, 4 mm slice thickness, 1 mm gap, 2323 cm field of view, and 128128 matrix. Conventional T1weighted (TR¼250 ms; TE¼50 ms) and T2-weighted (TR¼2480 ms; TE¼136 ms) images were also obtained for traditional image reading.
Data preprocessing
Materials and methods Study sample This study was approved by the participating local institutional review boards and performed according to the ethical standards set forth in 1964 in the Declaration of Helsinki. Both DR and healthy control patients were evaluated. A total of 21 patients (mean age 54.99.9 years) were enrolled in the DR group (proliferative and nonproliferative DR), including 11 women and 10 men. The
Data preprocessing was performed using the Data Processing Assistant for Resting-State Functional MR imaging (DPARSF; http://rfmri.org/DPARSF), which is based on the SPM8 software package (http://www.fil.ion.ucl.ac.uk), and the Resting-State fMRI Data Analysis Toolkit (REST). Two patients were excluded from the analysis because they had more than 2 mm of displacement or 2 of rotation in any direction. Linear regression was applied to remove other false variables, including the signal from the cerebral spinal fluid (CSF) and a region centred in the white matter (WM) of the brain. Individual T1-weighted structural imaging was
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
Z.-L. Wang et al. / Clinical Radiology xxx (2016) e1ee7 Table 1 Demographic and clinical features of the study participants. Characteristics
DR group (n¼21)
p-Value Control group t/x2 values (n¼16)
Age (years old) Gender (F/M) Duration of disease (years) Fasting glucose (mmol/l) HbA1c (%) HOMA-IR Diabetic nephropathy MMSE MoCA
54.99.9 11/10 9.485.01 8.611.54 8.431.71 3.371.08 4/21 28.161.09 21.690.70
54.85.7 9/7 5.68 0.98 5.62 0.94 2.340.97 28.990.71 25.181.88
0.04 0.06 2.46 3.92 8.50 -1.73 -13.42
0.970 0.815 0.019 < 0.001 < 0.001 0.093 < 0.001
*Data are presented as the mean SD. DR, diabetic retinopathy; HbA1c, haemoglobin A1c; HOMA-IR, homeostasis model assessment method-insulin resistance; MMSE, Mini Mental State Examinaton; MoCA, Montreal Cognitive Assessment.
co-registered to the mean of the realigned echo planar imaging images. The other steps included the removal of the first 10 time points from each patient’s data, section timing correction, and spatial normalisation to the Montreal Neurological Institute (MNI) space. Finally, the linear tendency of the time courses was smoothed using an algorithm based on an 8-mm full-width half maximum Gaussian kernel.
Data calculation
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and MoCA and MMSE scores, Pearson correlation analysis was performed using statistical software (SPM8, The FIL Methods Group, Shanghai, China). The threshold p-value for a statistically significant difference was <0.05, and the simulation software was used for correction. All statistical analyses were performed using SPSS version 19.0 (SPSS, Chicago, IL, USA).
Results Clinical demographic characteristics and neuropsychological data A total of 37 patients (20 women, 17 men) were included. The participant demographics of the DR and healthy control groups are listed in Table 1. The HbA1c levels and fasting glucose levels for the DR group were significantly increased compared to the healthy group (DR group versus healthy group; p<0.05). No difference in the MMSE scores was observed between the DR and healthy control groups. Compared to the healthy group, the MoCA scores of the DR group were significantly higher (p<0.01).
Group differences in the ALFF maps
The data calculation scheme was previously reported.8,15 A fast Fourier transform (FFT) was used to transform the time course into frequency. The square root of the power spectrum was computed and then averaged across 0.01e0.08 Hz at each voxel. This averaged square root was considered an ALFF measurement. For each voxel, raw ALFF values were divided by the global brain mean ALFF value for standardisation. Relative to the average ALFF values, standardised ALFFs for each voxel represented the degree of the raw value.
In the DR group, the ALFF values in the superior temporal gyrus, parietal lobe, bilateral occipital lobes, and inferior frontal gyrus were significantly higher than the global average ALFF values (Fig 1). The group differences are shown in Table 2. Increased ALFF values were seen the inferior/middle/bilateral superior occipital gyrus, right lingual gyrus, and precuneus in DR patients compared to the control group (p<0.01). The ALFF values were significantly lower in the DR group in the right posterior/anterior lobe of the cerebellum and the right fusiform, left parahippocampal, right superior temporal, right inferior parietal, and angular gyrus (p<0.01).
Statistical analysis
Correlation between ALFF values and clinical data
The normality of the quantitative variables was analysed using the ShapiroeWalk test. For normally distributed data, clinical differences between the patient and control group were evaluated using a t-test. For non-normal distributions of data or proportions, differences were analysed using the Wilcoxon signed-rank test or x2-test, respectively. A value of p<0.05 was regarded as significant. Differences in age, HbA1c levels, and MMSE scores between the patient and control groups were assessed by a two-sample t-test. A one-sample t-test was performed using the REST (resting-state) statistical analysis. The mean ALFF differences between the DR and healthy groups were assessed by a two-sample t-test. Simulation software (AlphaSim; National Institutes of Health, Bethesda, MD, USA) was used to correct these results, in which p<0.01 was considered significant after Bonferroni correction.7 To study the relationship between the ALFF values in the two groups (DR and healthy control groups) and the fasting plasma glucose levels, duration of disease, HbA1c levels,
The mean ALFF values in the right lingual gyrus and occipital lobe were negatively correlated with the MoCA scores in the DR group (p<0.01, simulation software corrected; Fig 2). A significant positive correlation was observed between the HbA1c levels and ALFF values in the right lingual and right precuneus gyrus (p<0.01, simulation software corrected; Fig 3). None of the regional ALFF values were significantly correlated with disease duration, fasting glucose levels, HOMA-IR (homeostasis model assessment method-insulin resistance), or the number connection test MMSE scores of patients in the DR group (all p<0.05, simulation software corrected).
Discussion In the present study, ALFF values were quantified to investigate spontaneous cerebral activity impairment in patients with DR. Significantly decreased ALFF values were observed in the DR group in their right posterior/anterior
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
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Figure 1 The red colour represents a higher ALFF value in patients with DR than in control subjects, whereas the blue colour represents a lower ALFF value.
Table 2 Cerebral regions showing amplitude of low-frequency fluctuations (ALFF) algorithm value differences between diabetics retinopathy (DR) patients and healthy controls. Brain region
Brodmann area
MNI coordinates x, y, z
Voxels
Mean ALFF value DR versus non-DR
t-Value
p-Value
R posterior lobe of cerebellum R anterior lobe of cerebellum L parahippocampal gyrus R fusiform/ superior temporal gyrus R inferior parietal/angular gyrus R/L superior/middle/ inferior occipital gyrus/R lingual gyrus Precuneus
d 38, 35 22, 37
21, 69, 60 18, 27, 18 48, 24, 54
1566 443 228
0.980.19 versus 1.140.18 1.130.19 versus 1.320.18 0.970.19 versus 1.100.17
2.59 3.89 2.36
0.014 < 0.001 0.024
39, 40 17, 18, 19
45, 42, 52 6, 96, 0
104 1055
1.030.23 versus 1.220.20 1.050.39 versus 0.900.16
2.31 3.08
0.026 0.004
7
18, 63, 39
162
1.150.16 versus 0.990.19
2.90
0.006
MNI, Montreal Neurological Institute; R, right; L, left.
cerebellar lobe and left parahippocampal, right fusiform, superior temporal, inferior parietal, and angular gyrus compared to the healthy control group. Increased ALFF values were observed in the DR group in the bilateral occipital lobe, right lingual gyrus, and precuneus. These results showed an association between clinical and neuropsychological parameters. The present findings provide novel evidence of an abnormal resting state during
spontaneous brain activity in DR patients. These findings might contribute to a further understanding of DR and brain functional alterations. Previous studies have shown abnormalities in spontaneous cerebral activity in functional areas in patients with T2DM7,9,16; however, ALFF data for brain injury in T2DM patients with retinopathy has not been reported yet. In the present study, DR was associated with regions of functional
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
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Figure 2 ALFF maps showing the correlation between ALFF values and MoCA scores in DR patients (p<0.01, corrected). MoCA scores in DR patients were negatively correlated with ALFF values in the right occipital lobe.
brain impairment, especially in the visual cortex, and impaired cognitive performance. The present results demonstrate that increased brain activity occurs not only in the bilateral occipital lobe of DR patients, but also in the right lingual gyrus and precuneus, which are associated with spontaneous brain activity in the visual centre. Liu et al.17 reported that abnormalities in spontaneous neural activity in primary open angle glaucoma (POAG) patients could be found in the visual cortex, and the decreased activity in the visual regions might be linked to abnormities in visual stimuli processing. An absence of stimulation in the visual centre of patients with DR may result in cortical structure modifications. Previous studies have indicated that developmental visual disorders affect the occipital cortex, e.g., albinism and amblyopia.18,19 Kitajima et al.20 showed a wider calcarine sulcus in patients with a variety of DR conditions using MRI, which suggested a possible link between cortical degeneration and visual field defects. Decreased stimulation of the visual centre may contribute to increased sensitivity in the area of the visual cortex. According to these results, increased ALFF values in the visual cortex may be due to the long-term decreases in the stimulation of the visual centre. Cui et al.7 reported decreased spontaneous visual activity in T2DM patients without retinopathy in a resting state compared to healthy
controls. Most of the patients in their study did not have any clinical visual or sensory alterations. Conversely, in accordance with the present study,14 it has been reported that increased brain activity in regions of T2DM patients is shown mainly in the visual centres, such as the cuneus, bilateral occipital lobes, fusiform gyrus, and precuneus. Cerebral functional area alterations in the visual cortex have been consistently observed in magnetic resonance spectroscopy (MRS) studies10,11 and in a diffusion-weighted imaging study.21 The relationship between retinopathy and brain impairment was well demonstrated in a previous study.11 The compensatory mechanism may temporarily ‘‘cover’’ damage in the functional areas before serious vision loss or blindness occurs. This might explain why a decrease in spontaneous brain activity in the visual areas of DR patients was not observed. Decreased voxels of grey matter density were observed in the right occipital lobe in patients with DR compared to the healthy controls.22 Therefore, the increased ALFF values in the superior/middle/inferior occipital gyrus may be related to a reduction in the grey matter density in patients with DR. The mechanism of the association between increased ALFF values in the occipital gyrus and DR was not clear. Hyperglycaemia may be an important mediator and may play an important role in brain functional impairment in DR patients. Hyperglycaemia
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
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Figure 3 ALFF maps showing the correlation between ALFF values and HbA1c levels in DR patients (p<0.01, corrected). HbA1c levels in the DR group were positively correlated with ALFF values in the precuneus and lingual gyrus.
leads to accelerated accumulation of glycosylation end products and potentially toxic glucose metabolites, which damage retinal microvessels by activating various interconnecting biochemical pathways.23 Retinopathy is generally considered a consequence of hyperglycaemia exposure.24 Apart from the increased ALFF values in the occipital cortex, increased activity was observed in the right lingual gyrus and the precuneus of DR patients in the present study. Previous studies have indicated that the precuneus plays an important role in the neural substrate of visual imagery, and it is primarily responsible for highly integrated tasks, including maintaining wakefulness and regulating visual spatial episodic memory.25,26 According to these findings, a potential relationship was proposed between abnormalities in visual processing areas and DR. Another important finding was the presence of reduced ALFF values in the anterior cerebellar lobe and posterior lobe of DR patients in this study. It has been reported that the cerebellum is associated with cognitive and executive functions.14,27 Studies have shown the distribution of various cognitive regions in the posterior lobe of the cerebellum and of motor functions in the anterior lobe.28 In a recent animal study, degenerative changes were also detected in the cerebellum of streptozotocin-treated
animals in an induced diabetic rat model, e.g., fragmentation of neurofilaments, disarrangement of myelin sheaths, and oligodendrocyte abnormalities.29 Therefore, the present results suggest that reduced spontaneous brain activity in the lobes of the cerebellum is associated with DR-related cognitive dysfunction. Decreased ALFF values were found in the left parahippocampal, right fusiform, superior temporal, inferior parietal, and angular gyrus. These findings were similar to the results of previous studies.17,30,31 These areas play important roles in cognitive function. The present results showed decreased activity in these regions, suggesting an impairment of cognitive function in DR patients. A recent study showed that neuronal necrosis, neuronal cell death, and gliosis contribute to increased ADC values in the brain functional regions of T2MD patients, suggesting that increased spontaneous brain activities are associated with neuronal necrosis and neuronal cell death.32 Abnormalities of the right occipital lobe and lingual gyrus were related to impaired cognitive performance on the MoCA in DR patients. The occipital lobe and lingual gyrus play a role in visual memory, attention, and other visual and cognitive functions.33 Nevertheless, in the present study, the brain functional area that negatively correlated with MoCA score in DR patients is influenced by many factors, such as high
Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012
Z.-L. Wang et al. / Clinical Radiology xxx (2016) e1ee7
blood sugar, HbA1c. Generally, the present results indicated that a stronger compensation results in greater damage to cognitive function. Furthermore, HbA1c levels were positively associated with ALFF values in the precuneus and lingual gyrus. Retinopathy is generally considered a consequence of exposure to hyperglycaemia. HbA1c values are used to monitor glycaemic control. The results of previous studies have shown a correlation between neuronal loss or dysfunction in the frontal cortex and parietal white matter and HbA1c levels.21,34 Therefore, the present results suggested that HbA1c levels influence cerebral function in DR patients. The present study had several limitations. First, the study sample was relatively small, which limits the generalisation of the study conclusions. Second, the spontaneous cerebral activity patterns in DR patients and healthy controls were analysed. Further studies should include T2MD without and with DR patients. Third, this was a cross-sectional study. It is important to investigate longitudinal changes in the visual region of DR patients. In summary, in the present study, widespread abnormalities of spontaneous resting state cerebral activity were demonstrated in the visual cortex of DR patients. The results demonstrated a significant correlation between neuropsychological impairment and clinical markers.
Acknowledgments This work was financially supported by the National Nature Science Foundation of China (grant nos. 81271384 and 81371623).
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Please cite this article in press as: Wang Z-L, et al., Abnormal spontaneous brain activity in type 2 diabetic retinopathy revealed by amplitude of low-frequency fluctuations: a resting-state fMRI study, Clinical Radiology (2016), http://dx.doi.org/10.1016/j.crad.2016.11.012