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Effectiveness of QSM Over R2* in Assessment of Parkinson's Disease - A Systematic Review
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.284377
Keywords: Iron deposition, Parkinson's disease, quantitative susceptibility mapping, R2* mapping, substantia nigraKey Message: Usefulness of QSM and R2* mapping in measuring iron deposition in Parkinson's disease
Parkinson's disease (PD) is a neurodegenerative disorder affecting 1--2 per 1000 of the population. Prevalence of PD is 1% of the population aged above 60 years. It is mainly associated with the degeneration of dopaminergic neurons in the substantia nigra (SN) and increased iron deposition.[1],[2],[3] The iron deposition has also been observed in other brain regions, such as red nuclei, globus pallidus, head of caudate, putamen, and thalamus.[4],[5],[6],[7] The diagnostic accuracy of PD based on clinical assessment was not satisfactory. Hence, in vivo imaging of brain content would serve as biomarker for PD diagnosis. With the advent of magnetic resonance imaging (MRI), the in vivo imaging of brain iron content had become possible. R2 and R2* relaxometry methods of MRI were useful in estimating the iron deposition in subtantia nigra and other gray matter nuclei in PD Patients. R2 and R2* maps were acquired using fast spin echo sequence (echo time msec, 8000/86; bandwidth, range, -62.5 to 62.5 kHz; four signals acquired) and a multiecho gradient echo sequence (45/4.0, 7.6, 11.2, 14.8, 18.4, 22.0, 25.6, 29.2, 32.8, 36.4, 40.0; bandwidth range, -62.5 to 62.5 kHz; flip angle, 15°).[8],[9],[10],[11],[12],[13] The relaxometry methods had disadvantage of considering both local and surrounding tissue susceptibilities. These inaccuracies had led to the development of novel technique called Quantitative Susceptibility Mapping (QSM). In QSM, the inhomogeneities from surrounding structures was removed by deconvolution method which helps in providing direct measure of local inhomogenities of the magnetic field. QSM maps were acquired using 3D multi Gradient Echo (GRE) data. The magnitude and phase images were obtained. The brain regions were segmented and finally QSM maps with suppressed streak artifacts were reconstructed from the background corrected phase images using morphology enabled dipole inversion (MEDI) sequence.[12],[13],[14],[15] The objective of this review was to compare QSM and R2* values in multiple deep gray matter nuclei in patients with PD and to determine if QSM can provide a more direct and accurate measure of iron content than R2* mapping, and more sensitive than R2* mapping to PD-related tissue changes.
Design This review was conducted according to the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The PRISMA includes a checklist to ensure transparent reporting of systematic reviews and a four-phase diagram.[16] Literature search strategy A comprehensive literature searches for relevant original research studies published between 2000 and 2018 was performed using PubMed-Medline, CINHAL, Science Direct, Scopus, and the Cochrane Library. The following keywords were used in the search: 'Parkinson's disease', 'R2* mapping', 'Quantitative Susceptibility Mapping', 'iron deposition', 'substantia nigra', 'red nucleus', 'Globus pallidus', 'Putamen,' and 'Head of Caudate nucleus'. Searches were limited to the English language and adult populations. Detailed methods of study retrieval from each database are shown in [Table 1]. References from retrieved studies were scanned for additional relevant studies, but none were identified.
Inclusion criteria Studies were included in this review if they fulfilled the below-mentioned selection criteria: Type of study
Type of participants The studies involved adult patients (above 18 years) with PD who underwent MRI brain which included QSM and R2*. Types of outcome Primary and secondary outcomes of effectiveness were assessed. Primary outcomes * Measurement of iron content in the regions of brain using MRI techniques such as R2* and QSM value. Secondary outcomes * Comparison of sensitivity between QSM and R2* values between PD and controls. Data extraction Two authors individually extracted data from each included study and any dissimilarity were resolved following a discussion. Data synthesis Data were assessed for quality of methods and outcomes.
A total of 327 studies were identified through the literature. Seven duplicate articles were removed. After assessment of titles and abstract, 310 studies were excluded because they did not meet the inclusion criteria. An additional five studies were excluded after assessing the full text because they did not meet the review criteria. The exclusion criteria were studies comparing iron content measured in brain using MRI (QSM and R2*) and postmortem, studies measuring iron content by QSM and R2* in other pathologies. Finally, five studies were included in the data extraction [Figure 1].
Sample characteristics The six reviewed studies involved 226 PD patients and 218 controls and the age group was 21–75. Both genders were included in all the studies. The majority of the patients were male. [Table 2] summarizes the sample characteristics of the reviewed studies.
Quality assessment Newcastle–Ottawa scale were utilized by two independent authors to assess the methodological qualities of the included studies. In the case of a disagreement a final decision was made by consensus with a third reviewer. Among the five studies none received the maximum quality score of nine points. Among five, one reviewed study had a methodological quality score of six, four had a score of five. All reviewed studies were case–control, specified patient characteristics, and reported inclusion and exclusion criteria. The detailed quality assessment is listed in [Table 3].
Structure by structure analyses of results from individual studies Substantia nigra An elevation of iron concentration was found in both R2* and QSM measurements in all the studies. Three studies also noted elevated in the iron concentration in pars compacta[17],[18],[19] and one study noted elevation in pars reticulate.[19] Red nucleus An elevation of iron concentration was found in QSM measurement of one study.[20] There was no significant iron content detected in R2* and QSM measurements in the other studies. Globus pallidus An elevation of iron concentration was found in QSM measurement of one study.[20] There was no significant iron content detected in R2* and QSM measurements in the other studies. Putamen There was no significant iron content detected in R2* and QSM measurements in all the studies. Caudate nucleus There was no significant iron content detected in R2* and QSM measurements in all the studies. Thalamus An elevation of iron concentration was found in QSM measurement of one study.[20] There was no significant iron content detected in R2* and QSM measurements in the other studies. Clinical correlation of R2* and QSM Out of five, three studies correlated R2* and QSM values with clinical parameters. One study found R2* values not correlated with any of the clinical parameters. QSM values in the substantia nigra pars compacta were highly correlated with the disease duration, levodopa equivalent daily dose [LEDD], unified Parkinson's disease rating scale (UPDRS).[18] Another longitudinal study found R2* values in substantia nigra correlated with UPDRS I and QSM values in substantia nigra got correlated with UPDRS III.[19] One study found several correlations R2* and QSM values in substantia nigra for UPDRS I, UPDRS II. The H–Y scale, LEDD was correlated with R2* and QSM values in substantia nigra.[20] Two studies did not correlate MRI measurements with clinical parameters.[17],[21] Correlation of R2* and QSM Three studies found that the accuracy was significantly higher for QSM than for R2*. The sensitivity of QSM compared to R2* in detecting the iron content deposition in substantia nigra of PD patients with controls with much larger dynamic range.[17],[18],[21]
Excessive Iron deposition is frequently associated with pathogenesis of PD.[22],[23],[24] Our study represents the first systemic review that analysis iron levels in various brain regions of PD patients by R2* and QSM. Our review confirmed that there is increase in iron deposition in substantia nigra and suggests iron deposition may also occur in the red nucleus, globus pallidus, and thalamus. Our study shows that QSM was sensitive in detecting the iron deposition in substantia nigra compared to R2*. R2* weighting depends on the varying magnetic field generated by both local tissue magnetic susceptibility and surrounding tissue susceptibility. These inaccuracies led to reduced sensitivity of predicting iron deposition levels.[25] Our review found that QSM values were highly correlated with disease condition especially with UPDRS II and UPDRS III which determine the motor activity and more sensitive measure for disease motor progression. Several postmortem studies had done in evaluation of iron deposition in Parkinson's disease. There is discrepancy in the results of R2* and QSM methods and postmortem results, the reason could be because post mortem measurements are usually done at late stages of PD.[7],[26] Hence, there is need for longitudinal studies using MRI methods to accurately assess the iron deposition in other brain regions apart from substantia nigra. The review showed that the limitations of R2* methods (disruptions due to calcifications, micro bleeds, and myelinated fiber's had been overcome by QSM and highly accurate in severing as diagnostic marker for PD.
Our study has few limitations. First, limited number of longitudinal studies involved in the review. Second, small sample size used.
Our review concludes that QSM has better accuracy than R2* method in detecting the iron deposition in different regions of brain in PD. However, due to discrepancies between QSM, R2* and postmortem results, large number of longitudinal studies in MRI would be required to confirm iron deposition in brain regions as biomarker for PD. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1]
[Table 1], [Table 2], [Table 3]
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