The Analysis of relation to brain iron deposition of Parkinson’s Disease using Quantitative Susceptibility Mapping

Article information

J Korean Med. 2024;45(1):148-162

Publication date (electronic) : 2024 March 1

doi : https://doi.org/10.13048/jkm.24010

Gyu-Ri Jeon ¹

, Han-Gyul Lee ²^,³

, Seung-won Kwon ²^,³

, Seung-Yeon Cho ¹^,³

, Woo-Sang Jung ²^,³

, Sang-Kwan Moon ²^,³

, Jung-Mi Park ¹^,³

, Chang-Nam Ko ¹^,³

, Seong-Uk Park ¹^,³^,

¹Stroke and Neurological Disorders Center, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea

²Department of Cardiology and Neurology of Korean Medicine, Kyung Hee University Medical Center, Seoul, Republic of Korea

³Department of Cardiology and Neurology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea

Correspondence to: Seong-Uk Park, Stroke and Neurological Disorders Center, Kyung Hee University Hospital at Gangdong, 892 Dongnam-ro, Gangdong-gu, Seoul, 05278, Republic of Korea, Tel: +82-2-440-6217, Fax: +82-2-440-7171, E-mail: seonguk.kr@gmail.com

Received 2024 January 20; Revised 2024 February 5; Accepted 2024 February 16.

Abstract

Objectives

This study aimed to investigate the levels of brain iron deposition in Parkinson’s disease (PD) patients using Quantitative Susceptibility Mapping (QSM) and to determine whether distinctions compared to the general population exist. Furthermore, we examined potential variations in iron deposition among different PD subtypes.

Methods

Structural brain imaging was conducted on 75 participants at Gangdong Kyung Hee University Hospital between August 2017 and May 2020. PD patients were categorized into Tremor Dominant (TD) and Postural Instability and Gait Difficulty (PIGD) subtypes. Voxel-based morphometry and QSM were employed to compare voxel-wise magnetic susceptibility across the entire brain between Normal Controls (NC) and PD groups. Subsequently, QSM values were compared between TD and PIGD groups.

Results

QSM values were compared among 46 PD patients and 23 normal controls, as well as between TD (n=22) and PIGD (n=24) groups. Voxel-based QSM analysis revealed no significant differences between groups. Similarly, ROI-based QSM analysis showed no significant distinctions.

Conclusions

No significant variations were observed between the PD patient group, NC group, or PD subtypes. This study systematically compared QSM values across a broad range of brain regions potentially linked to PD pathology. Additionally, the subdivision of the PD group into TD and PIGD subtypes for QSM-based iron deposition analysis represents a meaningful and innovative approach.

Keywords: Parkinson’s disease; QSM; Brain; Iron; Subtype

Fig. 1

Study flow chart

UPDRS, Unified Parkinson’s Disease Rating Scale; MMSE-K, Korean version of Mini-Mental State Examination; TD, Tremor dominant; PIGD, Postural instablility and gait difficulty; QSM, Quantitative susceptibiltiy mapping

Fig. 2

Voxel-based analysis of the area where increased QSM values between Normal control and PD group

(a), (b) SPM results: Height threshold T = 3.216386 {p<0.001(unc.)} Extent threshold k=50 voxels

Fig. 3

Voxel-based analysis of the area where increased QSM values between Normal control and PIGD group

(a), (b) SPM results: Height threshold T = 3.229296 {p<0.001(unc.)} Extent threshold k=50 voxels

Fig. 4

Voxel-based analysis of the area where increased QSM values between Normal control and Tremor dominant group

(a), (b) SPM results: Height threshold T = 3.229296 {p<0.001(unc.)} Extent threshold k=50 voxels

Fig. 5

Voxel-based analysis of the area where increased QSM values between PIGD and Tremor dominant group

(a), (b) SPM results: Height threshold T = 3.229296 {p<0.001(unc.)} Extent threshold k=50 voxels

Table 1

MRI Data Acquisition

Table 2

Baseline Characteristics of Participants

Table 3

Comparison of QSM Values between Normal Control and PD Group

Table 4

Comparison of QSM Values between Normal Control and PIGD Group

Table 5

Comparison of QSM Values between Normal Control and Tremor Dominant Group

Table 6

Comparison of QSM Values between PIGD and Tremor Dominant Group

Table 7

Comparison of QSM Values between Normal Control and PD Group

Table 8

Comparison of QSM Values between Normal Control, PIGD, and Tremor Dominant Group

References

1. Bernheimer H., Birkmayer W., Hornykiewicz O., Jellinger K., Seitelberger F.. 1973;Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20(4):415–55. https://doi.org/10.1016/0022-510X(73)90175-5.

2. Fearnley J. M., Lees A. J.. 1991;Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114(5):2283–2301. https://doi.org/10.1093/brain/114.5.2283.

3. de Rijk M. C., Rocca W. A., Anderson D. W., Melcon M. O., Breteler M. M., Maraganore D. M.. 1997;A population perspective on diagnostic criteria for Parkinson’s disease. Neurology 48(5):1277–81. https://doi.org/10.1212/WNL.48.5.1277.

4. Deistung A., Schweser F., Reichenbach J. R.. 2017;Overview of quantitative susceptibility mapping. NMR Biomed 30(4):e3569. https://doi.org/10.1002/nbm.3569.

5. Haacke E. M., Liu S., Buch S., Zheng W., Wu D., Ye Y.. 2014;Quantitative susceptibility mapping: current status and future directions. Magn Reson Imaging 33(1):1–25. https://doi.org/10.1016/j.mri.2014.09.004.

6. Ward R., Zucca F., Duyn J., Crichton R., Zecca L.. 2014;The role of iron in brain (160) ageing and neurodegenerative disorders. Lancet Neurol 13(10):1045–60. https://doi.org/10.1016/S1474-4422(14)70117-6.

7. Thenganatt M. A., Jankovic J.. 2014;Parkinson Disease Subtypes. JAMA Neurol 71(4):499–504. https://doi.org/10.1001/jamaneurol.2013.6233.

8. Sethi K.. 2008;Levodopa unresponsive symptoms in Parkinson disease. Mov Disord 23(S3):521–33. https://doi.org/10.1002/mds.22049.

9. Jankovic J., McDermott M., Carter J., Gauthier S., Goetz C., Golbeet L., et al. 1990;Parkinson Study Group. Variable expression of Parkinson’s disease: a base-line analysis of the DATATOP cohort. Neurology 40(10):1529–34. https://doi.org/10.1212/WNL.40.10.1529.

10. Rosenberg-Katz K., Herman T., Jacob Y., Giladi N., Hendler T., Hausdorff J. M.. 2013;Gray matter atrophy distinguishes between Parkinson disease motor subtypes. Neurology 80(16):1476–84. https://doi.org/10.1212/WNL.0b013e31828cfaa4.

11. Calne D. B., Snow B. J., Lee C.. 1992;Criteria for diagnosing Parkinson’s disease. Ann Neurol 32(S1):125–7. https://doi.org/10.1002/ana.410320721.

12. Bagher-Ebadian H., Jiang Q., Ewing J. R.. 2008;A modified fourier-based phase unwrapping algorithm with an application to MRI venography. J Magn Reson Imaging 27(3):649–52. https://doi.org/10.1002/jmri.21230.

13. Haacke E. M., Cheng N. Y., House M. J., Liu Q., Neelavalli J., Ogg R. J., et al. 2005;Imaging iron stores in the brain using magnetic resonance imaging. Magn Reson Imaging 23(1):1–25. https://doi.org/10.1016/j.mri.2004.10.001.

14. Braak H., Tredici K. D., Rub U., de Vos R. A., Jansen Steur E. N., Braak E.. 2003;Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24(2):197–211. https://doi.org/10.1016/S0197-4580(02)00065-9.

15. Sian-Hulsmann J., Mandel S., Youdim M. B., Riederer P.. 2011;The relevance of iron in the pathogenesis of Parkinson’s disease. J Neurochem 118(6):939–57. https://doi.org/10.1111/j.1471-4159.2010.07132.x.

16. Uchida Y., Kan H., Sakurai K., Arai N., Kato D., Kawashima S., et al. 2019;Voxel-based quantitative susceptibility mapping in Parkinson’s disease with mild cognitive impairment. Movement Disorders 34(8):1164–73. https://doi.org/10.1002/mds.27717.

17. Deh K., Nguyen T. D., Eskreis-Winkler S., Prince M. R., Spincemaille P., Gauthier S., et al. 2015;Reproducibility of quantitative susceptibility mapping in the brain at two field strengths from two vendors. J Magn Reson Imaging 42(6):1592–1600. https://doi.org/10.1002/jmri.24943.

18. Ravanfar P., Loi S. M., Syeda W. T., Van Rheenen T. E., Bush A. I., Desmond P., et al. 2021;Systematic Review: Quantitative Susceptibility Mapping (QSM) of Brain Iron Profile in Neurodegenerative Diseases. Front. Neurosci 15:618435. https://doi.org/10.3389/fnins.2021.618435.

19. Mazzucchi S., Frosini D., Costagli M., Del Prete E., Donatelli G., Cecchi P., et al. 2019;Quantitative susceptibility mapping in atypical Parkinsonisms. Neuroimage Clin 24:101999. https://doi.org/10.1016/j.nicl.2019.101999.

20. Guan X., Xuan M., Gu Q., Xu X., Huang P., Wang N., et al. 2017;Influence of regional iron on the motor impairments of Parkinson’s disease: a quantitative susceptibility mapping study. J Magn Reson Imaging 45(5):1335–42. https://doi.org/10.1002/jmri.25434.

21. Alves G., Larsen J. P., Emre M., Wentzel-Larsen T., Aarsland D.. 2006;Changes in motor subtype and risk for incident dementia in Parkinson’s disease. Mov Disord 21(8):1123–30. https://doi.org/10.1002/mds.20897.

22. Nègre-Pagès L., Grandjean H., Lapeyre-Mestre M., Montastruc J. L., Fourrier A., Lépine J. P., et al. 2010;Anxious and depressive symptoms in Parkinson’s disease: the French cross-sectional DoPaMiP study. Mov Disord 25(2):157–66. https://doi.org/10.1002/mds.22760.

23. Burn D. J., Landau S., Hindle J. V., Samuel M., Wilson K. C., Hurt C. S., et al. 2012;Parkinson’s disease motor subtypes and mood. Mov Disord 27(3):379–86. https://doi.org/10.1002/mds.24041.

24. Iijima M., Kobayakawa T., Saito S., Osawa M., Tsutsumi Y., Hashimotoet S., et al. 2011;Differences in odor identification among clinical subtypes of Parkinson’s disease. Eur J Neurol 18(3):425–29. https://doi.org/10.1111/j.1468-1331.2010.03167.x.

25. Moreau C., Delval A., Defebvre L., Dujardin K., Duhamel A., Petytet G., et al. 2012;Methylphenidate for gait hypokinesia and freezing in patients with Parkinson’s disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet Neurol 11(7):589–96. https://doi.org/10.1016/S1474-4422(12)70106-0.

26. Shahmaei V., Faeghi F., Mohammadbeigi A., Hashemi H., Ashrafi F.. 2019;Evaluation of iron deposition in brain basal ganglia of patients with Parkinson’s disease using quantitative susceptibility mapping. European Journal of Radiology Open 6:169–74. https://doi.org/10.1016/j.ejro.2019.04.005.

27. Chen Q., Chen Y., Zhang Y., Wang F., Yu H., Zhang C., et al. 2019;Iron deposition in Parkinson’s disease by quantitative susceptibility mapping. BMC Neurosci 20(23):1–8. https://doi.org/10.1186/s12868-019-0505-9.

Article information Continued

Fig. 1

Study flow chart

Fig. 2

Voxel-based analysis of the area where increased QSM values between Normal control and PD group

(a), (b) SPM results: Height threshold T = 3.216386 {p<0.001(unc.)} Extent threshold k=50 voxels

Fig. 3

Voxel-based analysis of the area where increased QSM values between Normal control and PIGD group

(a), (b) SPM results: Height threshold T = 3.229296 {p<0.001(unc.)} Extent threshold k=50 voxels

Fig. 4

Voxel-based analysis of the area where increased QSM values between Normal control and Tremor dominant group

(a), (b) SPM results: Height threshold T = 3.229296 {p<0.001(unc.)} Extent threshold k=50 voxels

Fig. 5

Voxel-based analysis of the area where increased QSM values between PIGD and Tremor dominant group

(a), (b) SPM results: Height threshold T = 3.229296 {p<0.001(unc.)} Extent threshold k=50 voxels

Table 1

MRI Data Acquisition

	Structural MRI
MR scanner	3T, Pihilips Achieva 5.3.0
TR	9.9 ms
TE	4.6 ms
FOV	240×240×190 (x, y, z)
Flip angle	8°
Voxel-size	1.0×1.0×1.0
Slice number	190

MRI : Magnetic resonance imaging; TR, repetition time; TE, echo time; FOV, field of view

Table 2

Baseline Characteristics of Participants

Characteristics	NC (n=23)	PIGD (n=24)	TD (n=22)	p-value
Age (years)	58.56 ± 9.93	66 ± 7.35	61.45 ± 9.80	0.023^*
CSFV	384.73 ± 83.41	413.70 ± 64.02	413.36 ± 66.67	0.567
GMV	615.08 ± 49.11	598.29 ± 59.75	619.27 ± 68.29	0.73
WMV	504.21 ± 59.51	504 ± 53.91	529.18 ± 74.47	0.893
TIV	1504.21 ± 135.27	1516 ± 115.83	1561.81 ± 165.11	0.665
MMSE-K	-	28.25 ± 1.79	28.86 ± 1.64	0.235
UPDRS Part II	-	9.17 ± 5.21	5.86 ± 4.45	0.026^*
UPDRS Part III	-	13.04 ± 10.13	10.05 ± 7.81	0.27

Data analysed by one-way ANOVA test. Shown as mean ± standard deviation. p*<0.05, statistically significant. NC, Normal control; PIGD, Postural instablility and gait difficulty; TD, Tremor dominant; FWE, Family wise error rate; CSFV, Cerebrospinal fluid volume; GMV, Gray matter volume; WMV, White matter volume; TIV, Total intracranial volume; MMSE-K, Korean version of Mini-Mental State Examination; UPDRS, Unified Parkinson’s Disease Rating Scale

Table 3

Comparison of QSM Values between Normal Control and PD Group

Group Analysis	Cluster size	Cluster location	BA	Talairach coordiantes			Z score
NC>PD	241	Left cerebellum Anterior lobe		−8.24	−50.61	−24.98	3.89
		Left cerebellum Posterior lobe Cerebellar tonsil		−5.36	−55.35	−34.39	3.57
	57	Right cerebrum Occipital lobe Precuneus	31	17.01	−60.2	24.09	3.87
	94			−6.09	−28.3	−41.75	3.78
	65	Right cerebrum Frontal lobe Medial frontal gyrus	6	7.03	35.46	36.58	3.62
	68	Right cerebrum Temporal lobe Superior temporal gyrus	38	37.22	7.58	−16	3.6
	56	Left cerebrum Temporal lobe Superior temporal gyrus	41	−39.2	−36.24	11.89	3.56
PD>NC	114	Right cerebrum Frontal lobe Inferior frontal gyrus	47	20.51	25.51	−6.47	3.72

NC, Normal control; PD, Parkinson’s disease; BA, Brodmann area.

Table 4

Comparison of QSM Values between Normal Control and PIGD Group

Group Analysis	Cluster size	Cluster location	BA	Talairach coordiantes			Z score
NC>PIGD	294	Right cerebellum Anterior lobe Dentate		8.89	−53.41	−25.86	4.239
	276	Left cerebellum Anterior lobe		−9.17	−50.65	−24.55	3.880
	72	Right cerebrum Frontal lobe	6	7.05	36.52	35.33	3.775
	70	Right cerebellum Posterior lobe		4.96	−50.29	−43.19	3.749
PIGD>NC	436	Right cerebrum Frontal lobe Inferior frontal gyrus	47	21.41	24.87	−4.72	4.481
	187	Left cerebellum Posterior lobe Cerebellar tonsil		−21.46	−46.36	−39.21	4.204
	202	Right cerebellum Posterior lobe Cerebellar tonsil		22.93	−49.51	−37.41	4.048
	104	Left cerebrum Sub-lobar insula	13	−32.98	21.92	13	3.638
	82	Left cerebrum Limbic lobe Parahippocampal gyrus	34	−10.51	−5.05	−14.85	3.594

NC, Normal control; PIGD, Postural instablility and gait difficulty; BA, Brodmann area.

Table 5

Comparison of QSM Values between Normal Control and Tremor Dominant Group

Group Analysis	Cluster size	Cluster location	BA	Talairach coordiantes			Z score
NC>TD	210	Right cerebrum Sub-lobar caudate		14.13	0.46	14.47	4.133
	77	Right cerebellum Anterior lobe culmen		33.87	−39.83	−21.44	3.997
	78	Left cerebrum Sub-lobar lentiform nucleus Putamen		−17.82	−0.91	15.15	3.756
		Left cerebrum Sub-lobar caudate		−12.34	−0.06	20.73	3.154
	84	Right cerebrum Temporal lobe Superior temporal gyrus	38	34.03	7.94	−19.62	3.637
	59	Left cerebellum Anterior lobe Dentate		−6.39	−54.73	−26.24	3.327
TD>NC	62	Left cerebrum Limbic lobe Anterior cingulate	24	−6.34	23.75	−6.64	3.855

NC, Normal control; TD, Tremor dominant; BA, Brodmann area.

Table 6

Comparison of QSM Values between PIGD and Tremor Dominant Group

Group Analysis	Cluster size	Cluster location	BA	Talairach coordiantes			Z score
PIGD>TD	236	Left cerebrum Parietal lobe Precuneus	31	−9.84	−62.47	24.32	3.714
		Left cerebrum Occipital lobe Cuneus	7	−9.96	−68.85	31.82	3.629
		Left cerebrum Occipital lobe Cuneus	18	−8.52	−75.32	25.82	3.350
TD>PIGD	114	Right cerebrum Limbic lobe Parahippocampal gyrus	30	29.36	−47.88	3.39	3.690

PIGD, Postural instablility and gait difficulty; TD, Tremor dominant; BA, Brodmann area.

Table 7

Comparison of QSM Values between Normal Control and PD Group

	NC (n=23)	PD (n=46)	p-value
Head of caudate nucleus	0.01176 ± 0.00999	0.00993 ± 0.00767	0.132
Insula	−0.0191 ± 0.00758	−0.0194 ± 1009550	0.365
Postcentral gyrus	−0.011 ± 0.00874	−0.0113 ± 0.00625	0.056
Precentral gyrus	−0.0097 ± 0.00861	−0.0097 ± 0.00627	0.071
Precuneus	−0.0103 ± 0.00913	−0.0107 ± 0.00627	0.033^*
Putamen	0.01921 ± 0.01906	0.01552 ± 0.01514	0.19
Red nucleus	0.06964 ± 0.03103	0.05945 ± 0.02819	0.572
Substania nigra	0.08147 ± 0.03995	0.09184 ± 0.03284	0.263
Thalamus	−0.0125 ± 0.00791	−0.0142 ± 0.00688	0.419
Globus pallidus	0.05542 ± 0.01682	0.05367 ± 0.0199	0.397

Data analysed by 2 sample t-test. Shown as mean ± standard deviation. p*<0.05, statistically significant. NC, Normal control; PD, Parkinson’s disease

Table 8

Comparison of QSM Values between Normal Control, PIGD, and Tremor Dominant Group

Total (n=69)	NC (n=23)	PIGD (n=24)	TD (n=23)	F-ratio	p-value
Head of caudate nucleus	0.01265	0.01106	0.00777	2.105	0.13
Insula	−0.01845	−0.01965	−0.01984	0.266	0.767
Postcentral gyrus	−0.009939	−0.01239	−0.01117	0.688	0.506
Precentral gyrus	−0.008613	−0.01108	−0.009318	0.78	0.463
Precuneus	−0.009251	−0.01139	−0.01103	0.578	0.564
Putamen	0.02219	0.01402	0.01403	2.176	0.122
Red nucleus	0.07286	0.06008	0.0554	2.247	0.114
Substania nigra	0.08542	0.09174	0.08781	0.183	0.833
Thalamus	−0.0122	−0.01463	−0.01404	0.641	0.53
Globus pallidus	0.05551	0.05705	0.04988	0.883	0.418

Data analysed by ANCOVA test. Shown as mean. p*<0.05, statistically significant. NC, Normal control; PIGD, Postural instablility and gait difficulty; TD, Tremor dominant