Quantitative assessment of iron deposition in Parkinson's disease using enhanced T2 star-weighted angiography
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.181532
Source of Support: None, Conflict of Interest: None
Background: It has been reported that R2* is a sensitive marker for iron deposition. The aim of this study was to quantitatively assess iron deposition in Parkinson's disease (PD) using changes of R2* in enhanced T2 star-weighted angiography (ESWAN) and to discuss the value of ESWAN for PD.
Keywords: Enhanced T2 star-weighted angiography; iron deposition; motor symptoms; nonmotor symptoms; Parkinson's disease
Parkinson's disease (PD) is a neurodegenerative disease characterized by various combinations of resting tremor, rigidity, bradykinesia, postural instability, and gait impairment and is expected to impose an increasing social and economic burden. In developed countries, the prevalence of PD is generally estimated at 0.3% of the entire population and approximately 1% in people over 60 years of age. Approximately 1.7 million people in China who are older than 55 years suffer from this disease., The primary pathogenesis of PD is the degeneration and deficiency of intracranial nigral dopaminergic neurons. A number of studies have reported that while performing autopsies on PD patients, researchers found iron deposition in the substantia nigra (SN) of the patients. Some scholars believe that the amount of iron deposition at specific intracranial locations is related to the disease progression.
A diagnosis of PD is primarily based on clinical symptoms, and a good response of the symptoms to levodopa is supportive of a diagnosis of PD. Although a reliable and applicable diagnostic test or marker for PD is not yet available, enhanced T2 star-weighted angiography (ESWAN) may be able to provide a superior assessment of the differences in ESWAN-based parameters between the different stages of PD. This modern technique may potentially lead to future improvements in the diagnosis and prognostication of PD, based on a better understanding of the association between iron deposition and PD.
The ESWAN technique is a new type of susceptibility-weighted sequence that provides significant advantages over the conventional susceptibility-weighted imaging (SWI) method, including an enhanced susceptibility sensitivity, a high spatial resolution, a high signal-to-noise ratio, and a reduced chemical shift artifact. The method is based on the differences between the magnetic susceptibility of different tissues and is a contrast enhancement technique that can reflect the magnetized properties of tissues. R2* (R2* = 1/T2*) reflects the combination of the nuclear interaction and field inhomogeneity caused by the presence of paramagnetic or diamagnetic substances such as iron. An assessment of iron deposition and white matter maturation in infant brains has also been performed by using ESWAN: R2* and compared with phase values.
Iron is an indispensable trace element in the human body and is the key component of heme in the pigment proteins of cells. Iron participates in various processes including deoxyribonucleic acid synthesis, gene expression, myelination, neurotransmission, and mitochondrial electron transport during the respiratory process. Iron becomes toxic when it appears in the tissues in an unbound form, resulting in damage to and necrosis of tissues and cells.,,, This is because of its high paramagnetic properties that induces a magnetic susceptibility that is much higher than that of the surrounding tissues.
Past studies have shown that iron deposition in the brain is primarily concentrated in locations such as the globus pallidus (GP), SN, red nuclei, caudate nuclei, and putamina., Consequently, our study evaluated deep gray nuclei, including bilateral SN, GP, red nuclei, putamina, caudate nuclei, and thalami. The aim of the present investigation was to determine the diagnostic sensitivity of ESWAN in PD for its potential clinical application and to evaluate the correlation between iron deposition in specific tissues and clinical symptoms.
Fifty-four patients with PD were recruited for the study between March 2013 and December 2014. Twenty-eight healthy sex- and age-matched volunteers were included in the control group. The patients were referred from the Neurology Department of Tongji Hospital for clinical diagnosis. All of these patients underwent a thorough clinical examination and neuropsychological tests. The examination included the Hoehn and Yahr (H and Y) scales, unified PD rating scale III (UPDRS III), nonmotor symptom scale (NMSS), and mini mental state examination (MMSE) scale, which were validated in China.
The motor functions were assessed using the UPDRS III. The NMSS is currently the most authoritative rating scale for determining nonmotor symptoms (NMSs) of PD patients. The MMSE is the test most widely applied for screening of cognitive deficits.
The scales were performed before the imaging was obtained, and the scorers were blinded to the imaging results.
All experiments were conducted in accordance with the Declaration of Helsinki, with adequate understanding and written consent of the patients and with the ethical approval of the Medical Research Ethics Committee of Tongji Hospital, Huazhong University of Science and Technology.
Magnetic resonance imaging equipment
A Discovery MR750 3.0T magnetic resonance imaging (MRI) system with an eight-channel phased array head coil was used. The repetition time was 55·4 ms, and the echo time was 5·7 ms. The field of view was 240 mm × 240 mm. The matrix was 416 × 320. The number of excitations was 0.7. The function tool software was used to process the image information and to produce corrected afterimages.
Data processing and analysis of enhanced T2 star-weighted angiography image data
The function tool software was used for postprocessing all ESWAN images. High-pass filtered phase and magnitude images were generated and stored for each patient. All the images were processed and analyzed by a single neuroradiologist, and the investigators were blinded to the patient status. The R2* anatomical regions were measured bilaterally and SN, GP, red nucleus, putamen, caudate nucleus, and thalamus (THA) were included.
Correlation of putative iron content, as represented by changes in R2* and its phases, has been carried out with age in the deep gray matter of healthy adults. In the present study, the method of drawing regions of interest (ROIs) in the map was carried out as follows: Five layers of the cross section of the ESWAN sequence, on which the images were the clearest, were selected. A single slice that displayed the largest area and the most well-defined border was selected for each structure and analyzed. As a further condition, slices that were severely affected by artifacts were not used. The bright boundaries outside the structures were also avoided because this large positive phase shift was most likely associated with the iron-induced dipolar field patterns in the tissue. Structures were magnified to make the boundaries easier to determine, and the area of the structure was more accurately demarcated. The measurement range, which was drawn manually, included all the visible measured structural ranges on the layer. [Figure 1],[Figure 2],[Figure 3],[Figure 4] show the measurement range. The two sides were measured separately, and the mean R* value of each location on each side was measured. The weighted mean value of the R* of each location was measured. The equation used was as follows: The area of the first layer × the signal value of the first layer + the area of the second layer × the signal value of the second layer + the number of z × z)/the total area.
The GraphPad Prism 5 version 5.01 statistical software was used for the statistical analysis. We used the R* value to determine the iron deposition of the substantia nigra, GP, red nuclei, putamina, caudate nuclei, and thalami. Group differences between patients and controls as well as patients with HY = 1 and those with HY >1, were calculated with two sample t-test statistics. Correlations were tested using Pearson's correlation test. The significance level was set at P > 0.05.
The 54 PD patients included 30 males and 24 females, with their ages ranging from 42 to 86 years (median = 59 years). The mean of H and Y stage was 2.037 ± 1.081, with 22 patients in HY1, 16 patients in HY2, 8 patients in HY3, and 8 patients in HY4. The total range of the UPDRS motor score was from 3 to 28 (median = 16.85 ± 6.986). The total range of the NMSS motor scores was from 3 to 186 (median = 51.30 ± 39.822). The total range of the MMSE scores was from 15 to 30 (median = 23.40 ± 4.952), and the mean duration of the course of the disease was 3.0 ± 3.4 years.
The differences between the patients and healthy volunteers are shown in [Table 1] for the R* values in ESWAN. There were significant differences between the PD patients and the healthy individuals in the control group in terms of the SN and red nuclei (P < 0.05). No significant difference, however, was obtained between the PD patients and the patients in the control group in terms of the GP, putamina, caudate nuclei, and thalami (P > 0.05).
There was a significant difference between the HY1 and HY2-4 patients in terms of the signal values of the SN. No significant difference in terms of the red nuclei, putamina, GP, caudate nuclei, and thalami was found (P > 0.05) [Table 2].
R2* and motor symptoms
The R* signal values of the red nuclei, SN, caudate nuclei, putamina, GP, and thalami of the PD patients measured using the ESWAN sequence were not correlated with the UPDRS III scores. However, the signal values of the SN of the patients with the HYscale score >1 slightly correlated with the UPDRS III scores [Table 3],[Table 4],[Table 5] and [Figure 5].
The R*and nonmotor symptoms
The R* signal values of the red nuclei, SN, caudate nuclei, putamina, GP, and thalami of the PD patients measured using the ESWAN sequence were not correlated with the NMSS and MMSE scores. The R* signal values of the patients (HY >1) were also not correlated with the NMSS and MMSE scores [Table 6],[Table 7],[Table 8],[Table 9],[Table 10],[Table 11].
The ESWAN sequence was used to assess the changes of the R2* values in the deep gray nuclei. We qualified R2* values as an assessment tool for the presence of iron deposition in the deep gray nuclei in the patient group. We compared each side of interest of the PD patients with the corresponding side of the control group and found significant differences in the R* values of the SN and red nuclei (P < 0.05). Comparison of the results showed that the iron contents in the red nuclei and SN of the PD patients increased significantly. The results demonstrated herein are in agreement with previous studies. In Zhang's study, iron concentrations in the SN increased more significantly. In the study by Rossi's et al., disease-related changes were present in the SN and GP. However, the reason for some of the differing results may be methodological differences between the ESWAN sequences used, and the anomalous iron deposition in the red nuclei and SN of the PD patients assessed using the ESWAN sequence, a finding which may be beneficial for the early diagnosis of PD. In the study by Haller et al., it was found that the increased signals on susceptibility weighted imaging (SWI) in bilateral thalami and the left SN in PD patients versus other Parkinsonism More Details states indicated that SWI may help in distinguishing between PD and other forms of Parkinsonism states. This finding also shows that SWI has advantages in the diagnosis of PD.
We compared the same sides of the HY1 patients and HY >1 patients, discovering a significant difference in the R* values obtained from the SN. Anomalous iron deposition in the brain might be caused by the abnormal function or disrupted expression of brain iron metabolism-related proteins induced by genetic or nongenetic factors. In Zhang's study, iron concentrations in the SN increased more significantly. Furthermore, on comparing the R* values obtained from the HY1 patients and HY >1 patients, we found a discrepancy between their R* values. We hypothesize that iron concentrations in the SN may represent the severity of PD.
A number of previous studies have mentioned the correlation between iron deposition and the diagnosis of PD, as has been confirmed in the present study. However, there are varying opinions on whether there is a correlation between iron deposition and the clinical motor symptoms of PD. Some studies have indeed discovered a correlation between the low-density regions in certain characteristic locations and motor symptoms. In addition, some experiments have discovered that the UPDRS III scores did not correlate with the findings in SN but slightly correlated with the findings in GP.
Based on our research results, we found that the R* values of the SN of all the patients did not correlate with their UPDRS III scores; in addition, the R* values of the SN of the patients in HY scale score of 1 also did not correlate with their UPDRS III scores; whereas, the R* signal values of the SN of the patients in HY scale score of >1 slightly correlated with their UPDRS III scores. We believe that the reason for the partial correlation with higher HY scale scores but with no overall correlation was that the UPDRS III scores of patients in an earlier stage of their disease were relatively low. Moreover, the number of HY1 patients constituted a relatively large proportion of the total number of patients, which affected the trend of the overall correlation. We believe that the R* values of the SN of HY 2–4 patients slightly correlated with their UPDRS III scores. Based on this correlation, we hypothesize that for PD patients, the R2* decrease is probably a marker of PD-related pathology. Based on the above results and our analysis, we propose that the assessment of the amount of anomalous iron deposition can be used as an objective prediction index for determining the severity of motor symptoms in patients with PD. However, there is no unified opinion amongst the various studies regarding a quantification standard, which is a problem that we shall strive to address and resolve in our future work.
In this study, we found that the R* values of the ROIs of the PD patients did not correlate with their NMSS and MMSE scores. In addition, in the patients in the HY scale score of >1, these values did not correlate with their NMSS scores and MMSE scores. NMSs are common clinical manifestations of PD, and the NMSS is a relatively authoritative rating scale for determining the severity of NMSs in patients with PD; in addition, the NMSS can be used to evaluate different types of NMSs, which are the primary cause of PD disabilities., Among the PD patients, 90% have NMS-related manifestations including psychosis, anomalous autonomic nervous system manifestations, sleep disorders, and paresthesia (e.g., pain and visual changes).
We found that the anomalous iron deposition did not significantly correlate with either the NMSS scores or the MMSE scores. Thus, it is possible that although the extent and location for anomalous iron deposition may correlate with the motor symptoms of PD, it may not correlate with the NMSs of the patients. It is considered in neuropathology that the pathogenesis of PD may not be limited to the dopaminergic neural system but may be related to the nuclei and to locations that do not directly control motor functions, including the dorsal nuclei of the vagus nerve, locus coeruleus, raphe nuclei, hypothalami, olfactory tubercles, and limbic cortices., Certain researchers believe that the pathogenesis of PD is related to the peripheral sympathetic nervous system, including the sympathetic ganglion, cardiac sympathetic efferent neurons, and the myenteric plexus of the intestinal tract. The cause of NMSs may be based on the involvement of dorsal nuclei of the vagus nerve, locus coeruleus, raphe nuclei, hypothalami, olfactory tubercles, and limbic cortices. This might explain why iron deposition within the red nuclei, caudate nuclei, putamina, GP, and thalami did not correlate with NMSs in this study. Thus, to further elucidate and alleviate the cause of NMSs of PD and thereby improve the quality of life for patients with PD, it is necessary to further study the PD-related nuclei and locations that do not directly control motor functions.
When ESWAN is used to quantitatively analyze iron concentration in deep brain grey matter nuclei, the iron concentrations in these regions may correlate with the severity of PD. The anomalous iron deposition in the PD patients in HY scale score of >1 at the SN correlated with the UPDRS III score. Whether it is possible to use the amount of anomalous iron deposition as an objective index for determining the severity of PD patients' motor symptoms, and whether anomalous iron deposition at other locations is related to the NMSs remain problems for further discussion and investigation. As a relatively new MRI technique, the ESWAN technique provides special advantages in determining iron deposition in the brain and enables the establishment of an early and sensitive diagnosis of PD.
Our research sample size was relatively small. A axial comparison method at one point in time was used to compare the anomalous iron deposition. Currently, our team is carrying out a longitudinal comparison of the intracranial iron changes in PD patients, trying to compare their MRI findings with their changing ages and disease conditions. The present study provided only a preliminary assessment of the usefulness of ESWAN in the detection of iron levels in PD patients, and we are currently investigating other imaging methods with which ESWAN will be compared to examine the advantages of the latter sequence in determining anomalous iron deposition in the brain. Our team is currently also studying whether or not the iron deposition amounts and rates change after patients start taking anti-Parkinsonism drugs.
No financial support or sponsorship.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11]