[en] Parkinson’s disease is a neurodegenerative synucleinopathy characterized by the degeneration of neuromelanin-containing dopaminergic neurons and deposition of iron in the substantia nigra (SN). How regional neuromelanin (NM) loss and iron accumulation within specific areas of SN relates to nigro-striatal dysfunction needs to be clarified. We measured dopaminergic function in pre- and post-commissural putamen by [18F]DOPA PET in twenty-three Parkinson’s disease (PD) patients and 23 healthy control (HC) participants in whom NM content and iron load was assessed in medial and lateral SN, respectively by neuromelanin-sensitive and quantitative R2* MRI. Data analysis consisted of voxelwise regressions testing the group effect and its interaction with NM or iron signals. In PD patients, R2* was selectively increased in left lateral SN as compared to healthy participants, suggesting a local accumulation of iron in Parkinson’s disease. By contrast, NM signal differed between PD and HC, without specific regional specificity within SN. Dopaminergic function in posterior putamen decreased as R2* increased in lateral SN, indicating that dopaminergic function impairment progresses with iron accumulation in the SN. Dopaminergic function was also positively correlated with NM signal in lateral SN, indicating that dopaminergic function impairment progresses with depigmentation in the SN. A complex relationship was detected between R2* in the lateral SN and NM signal in the medial substantia nigra. In conclusion, multimodal imaging reveals regionally-specific relationships between iron accumulation and depigmentation within the SN of Parkinson’s disease and provides in vivo insights in its neuropathology.
Research Center/Unit :
GIGA CRC (Cyclotron Research Center) In vivo Imaging-Aging & Memory - ULiège
Disciplines :
Neurology
Author, co-author :
DEPIERREUX, Frédérique ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de neurologie
PARMENTIER, Eric ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de neurologie
Degueldre, Christian ; Université de Liège - ULiège > GIGA CRC In vivo Imaging - Aging & Memory
Balteau, Evelyne ; Université de Liège - ULiège > GIGA CRC In vivo Im. - Neuroimaging, data acquisi. & proces.
SALMON, Eric ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Centre de jour interdisciplinaire des troubles de la mémoire
Phillips, Christophe ; Université de Liège - ULiège > GIGA CRC In vivo Im. - Neuroimaging, data acquisi. & proces.
Bahri, Mohamed Ali ; Université de Liège - ULiège > GIGA CRC In vivo Imaging - Aging & Memory
MAQUET, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de neurologie
GARRAUX, Gaëtan ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Groupe des mouvements anormaux (Movere)
Erkkinen, M. G., Kim, M. & Geschwind, M. D. Clinical neurology and epidemiology of the major neurodegenerative diseases. Cold Spring Harb. Perspect. Biol. 10, a033118 (2018). DOI: 10.1101/cshperspect.a033118
Braak, H., Sandmann-Keil, D., Gai, W. & Braak, E. Extensive axonal Lewy neurites in Parkinson’s disease: a novel pathological feature revealed by α-synuclein immunocytochemistry. Neurosci. Lett. 265, 67–69 (1999). DOI: 10.1016/S0304-3940(99)00208-6
Dickson, D. W. et al. Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol. 8, 1150–1157 (2009). DOI: 10.1016/S1474-4422(09)70238-8
Halliday, G., Lees, A. & Stern, M. Milestones in Parkinson’ s disease–clinical and pathologic features. Mov. Disord. 26, 1015–1021 (2011). DOI: 10.1002/mds.23669
Hirsch, E. C., Graybiel, A. M. & Agid, Y. Melanized dopaminergic neurons are differentially affected in Parkinson’s disease. Nature 334, 345–348 (1988). DOI: 10.1038/334345a0
Postuma, R. et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov. Disord. 30, 1591–1601 (2015). DOI: 10.1002/mds.26424
Cheng, H. C., Ulane, C. M. & Burke, R. E. Clinical progression in Parkinson disease and the neurobiology of axons. Ann. Neurol. 67, 715–725 (2010). DOI: 10.1002/ana.21995
Hughes, A. J., Daniel, S. E., Kilford, L. & Lees, A. J. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55, 181–184 (1992). DOI: 10.1136/jnnp.55.3.181
Rizzo, G. et al. Accuracy of clinical diagnosis of Parkinson disease: a systematic review and meta-analysis. Neurology 86, 566–576 (2016). DOI: 10.1212/WNL.0000000000002350
Snow, B. J. et al. Human positron emission tomographic [18F]Fluorodopa studies correlate with dopamine cell counts and levels. Ann. Neurol. 34, 324–330 (1993). DOI: 10.1002/ana.410340304
Morrish, P. K., Sawle, G. V. & Brooks, D. J. An [18F]dopa-PET and clinical study of the rate of progression in Parkinson’s disease. Brain 119, 585–591 (1996). DOI: 10.1093/brain/119.2.585
Morrish, P. K., Sawle, V. & Brooks, J. Clinical and [18F]dopa PET findings in early Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 59, 597–600 (1995). DOI: 10.1136/jnnp.59.6.597
Sasaki, M. et al. Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson’s disease. Neuroreport 17, 1215–1218 (2006). DOI: 10.1097/01.wnr.0000227984.84927.a7
Kitao, S. et al. Correlation between pathology and neuromelanin MR imaging in Parkinson’s disease and dementia with Lewy bodies. Neuroradiology 55, 947–953 (2013). DOI: 10.1007/s00234-013-1199-9
Martin-Bastida, A., Pietracupa, S. & Piccini, P. Neuromelanin in parkinsonian disorders: an update. Int. J. Neurosci. 127, 1116–1123 (2017). DOI: 10.1080/00207454.2017.1325883
Cassidy, C. M. et al. Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain. Proc. Natl Acad. Sci. USA 116, 5108–5117 (2019). DOI: 10.1073/pnas.1807983116
Pyatigorskaya, N. et al. Iron imaging as a diagnostic tool for Parkinsonas disease: a systematic review and meta-analysis. Front. Neurol. 11, 1–16 (2020). DOI: 10.3389/fneur.2020.00366
Damier, P., Hirsch, E. C., Agid, Y. & Graybiel, A. M. The substantia nigra of the human brain: I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry. Brain 122, 1421–1436 (1999). DOI: 10.1093/brain/122.8.1421
Damier, P., Hirsch, E. C., Agid, Y. & Graybiel, A. M. The substantia nigra of the human brain II. Patterns of loss of dopamine-containing neurons in Parkinson’ s disease. Brain 122, 1437–1448 (1999).
Kish, S. J., Shannak, K. & Hornykiewicz, O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. N. Engl. J. Med. 318, 876–880 (1988). DOI: 10.1056/NEJM198804073181402
Hallgren, B. & Sourander, P. The effect of age on the non-haemine iron in the human brain. J. Neurochem. 3, 41–51 (1958). DOI: 10.1111/j.1471-4159.1958.tb12607.x
Martin, W. R. W., Wieler, M. & Gee, M. Midbrain iron content in early Parkinson disease: a potential biomarker of disease status. Neurology 70, 1411–1417 (2008). DOI: 10.1212/01.wnl.0000286384.31050.b5
Trujillo, P. et al. Contrast mechanisms associated with neuromelanin-MRI. Magn. Reson. Med. 78, 1790–1800 (2017). DOI: 10.1002/mrm.26584
Lehéricy, S., Sharman, M. A., Dos Santos, C. L., Paquin, R. & Gallea, C. Magnetic resonance imaging of the substantia nigra in Parkinson’s disease. Mov. Disord. 27, 822–830 (2012). DOI: 10.1002/mds.25015
Biondetti, E. et al. Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson’s disease. Brain 143, 2757–2770 (2020). DOI: 10.1093/brain/awaa216
Langley, J. et al. Reproducible detection of nigral iron deposition in 2 Parkinson’s disease cohorts. Mov. Disord. 34, 416–419 (2019). DOI: 10.1002/mds.27608
Xing, Y., Sapuan, A., Dineen, R. A. & Auer, D. P. Life span pigmentation changes of the substantia nigra detected by neuromelanin-sensitive MRI. Mov. Disord. 33, 1792–1799 (2018). DOI: 10.1002/mds.27502
Chen, X. et al. Simultaneous imaging of locus coeruleus and substantia nigra with a quantitative neuromelanin MRI approach. Magn. Reson. Imaging 32, 1301–1306 (2014). DOI: 10.1016/j.mri.2014.07.003
Langley, J. et al. A multicontrast approach for comprehensive imaging of substantia nigra. Neuroimage 112, 7–13 (2015). DOI: 10.1016/j.neuroimage.2015.02.045
Isaias, I. U. et al. Neuromelanin imaging and dopaminergic loss in Parkinson’s disease. Front. Aging Neurosci. 8, 1–12 (2016). DOI: 10.3389/fnagi.2016.00196
Schwarz, S. T. et al. T1-weighted MRI shows stage-dependent substantia nigra signal loss in Parkinson’s disease. Mov. Disord. 26, 1633–1638 (2011). DOI: 10.1002/mds.23722
Martín-Bastida, A. et al. Relationship between neuromelanin and dopamine terminals within the Parkinson’s nigrostriatal system. Brain 142, 2023–2036 (2019). DOI: 10.1093/brain/awz120
Ohtsuka, C. et al. Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson’s disease using neuromelanin-sensitive MR imaging. Neurosci. Lett. 541, 93–98 (2013). DOI: 10.1016/j.neulet.2013.02.012
Schwarz, S. T., Xing, Y., Tomar, P., Bajaj, N. & Auer, D. P. In Vivo assessment of brainstem depigmentation in Parkinson disease: potential as a severity marker for multicenter studies. Radiology 283, 789–798 (2017). DOI: 10.1148/radiol.2016160662
Lhermitte, J., Kraus, W. M. & McAlpine, D. On the occurrence of abnormal deposits of iron in the brain in parkinsonism with special reference to its localisation. J. Neurol. Neurosurg. Psychiatry S1-5, 195–208 (1924). DOI: 10.1136/jnnp.s1-5.19.195
Sofic, E. et al. Increased iron (II1) and total iron content in post mortem substantia nigra of parkinsonian brain. J. Neural Transm. 74, 199–205 (1988). DOI: 10.1007/BF01244786
Hirsch, E. C., Brandel, J. ‐P., Galle, P., Javoy‐Agid, F. & Agid, Y. Iron and aluminum increase in the substantia nigra of patients with Parkinson’s disease: an X‐ray microanalysis. J. Neurochem. 56, 446–451 (1991). DOI: 10.1111/j.1471-4159.1991.tb08170.x
Uitti, R. J. et al. Regional metal concentrations in parkinson’s disease, other chronic neurological diseases, and control brains. Can. J. Neurol. Sci. 16, 310–314 (1989). DOI: 10.1017/S0317167100029140
Rossi, M. et al. Brain iron deposition and sequence characteristics in parkinsonism. Investig. Radiol. 45, 795–802 (2010). DOI: 10.1097/RLI.0b013e3181ec9c96
Langkammer, C. et al. Quantitative MR imaging of brain iron: a postmortem validation study. Radiology 257, 455–462 (2010). DOI: 10.1148/radiol.10100495
Langkammer, C. et al. Quantitative susceptibility mapping (QSM) as a means to measure brain iron? A post mortem validation study. Neuroimage 62, 1593–1599 (2012). DOI: 10.1016/j.neuroimage.2012.05.049
Baudrexel, S. et al. Quantitative mapping of T1 and T2* discloses nigral and brainstem pathology in early Parkinson’s disease. Neuroimage 51, 512–520 (2010). DOI: 10.1016/j.neuroimage.2010.03.005
Pyatigorskaya, N. et al. High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry. Mov. Disord. 30, 1077–1084 (2015). DOI: 10.1002/mds.26218
Reimão, S. et al. Magnetic resonance correlation of iron content with neuromelanin in the substantia nigra of early-stage Parkinson’s disease. Eur. J. Neurol. 23, 368–374 (2016).
Langley, J., Huddleston, D. E., Liu, C. J. & Hu, X. Reproducibility of locus coeruleus and substantia nigra imaging with neuromelanin sensitive MRI. Magn. Reson. Mater. Phys., Biol. Med. 30, 121–125 (2017). DOI: 10.1007/s10334-016-0590-z
Wang, J. et al. Meta-analysis of brain iron levels of Parkinson’ s disease patients determined by postmortem and MRI measurements. Nat. Publ. Gr. 1–13 (2016). https://doi.org/10.1038/srep36669.
Bagnato, F. et al. Untangling the R2* contrast in multiple sclerosis: a combined MRI-histology study at 7.0 Tesla. PLoS ONE 13, 1–19 (2018). DOI: 10.1371/journal.pone.0193839
Galazka-Friedman, J. et al. Iron in parkinsonian and control substantia nigra? A mössbauer spectroscopy study. Mov. Disord. 11, 8–16 (1996). DOI: 10.1002/mds.870110104
Hare, D. J. & Double, K. L. Iron and dopamine: a toxic couple. Brain 139, 1026–1035 (2016). DOI: 10.1093/brain/aww022
Zecca, L. et al. The role of iron and molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc. Natl Acad. Sci. USA 101, 9843–9848 (2004). DOI: 10.1073/pnas.0403495101
Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R. & Zecca, L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 13, 1045–1060 (2014). DOI: 10.1016/S1474-4422(14)70117-6
Zucca, F. A. et al. Neuromelanin of the human substantia nigra: an update. Neurotox. Res. 25, 13–23 (2014). DOI: 10.1007/s12640-013-9435-y
Jellinger, K., Paulus, W., Grundke-Iqbal, I., Riederer, P. & Youdim, M. B. H. Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases. J. Neural Transm. Park. Dis. Dement. Sect. 2, 327–340 (1990). DOI: 10.1007/BF02252926
Azuma, M. et al. Lateral asymmetry and spatial difference of iron deposition in the substantia nigra of patients with Parkinson disease measured with quantitative susceptibility mapping. Am. J. Neuroradiol. 37, 782–788 (2016). DOI: 10.3174/ajnr.A4645
Arribarat, G. et al. Substantia nigra locations of iron-content, free-water and mean diffusivity abnormalities in moderate stage Parkinson’s disease. Park. Relat. Disord. 65, 146–152 (2019). DOI: 10.1016/j.parkreldis.2019.05.033
Stoessl, A. J., Lehericy, S. & Strafella, A. P. Imaging insights into basal ganglia function, Parkinson’s disease, and dystonia. Lancet 384, 532–544 (2014). DOI: 10.1016/S0140-6736(14)60041-6
Kaasinen, V. & Vahlberg, T. Striatal dopamine in Parkinson disease: a meta-analysis of imaging studies. Ann. Neurol. 82, 873–882 (2017). DOI: 10.1002/ana.25103
Kuya, K. et al. Correlation between neuromelanin-sensitive MR imaging and 123I-FP-CIT SPECT in patients with parkinsonism. Neuroradiology 58, 351–356 (2016). DOI: 10.1007/s00234-016-1644-7
Okuzumi, A. et al. Neuromelanin or DaT-SPECT: which is the better marker for discriminating advanced Parkinson’s disease? Eur. J. Neurol. 26, 1408–1416 (2019). DOI: 10.1111/ene.14009
Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8, 382–397 (2009). DOI: 10.1016/S1474-4422(09)70062-6
Morrish, P. K., Rakshi, J. S., Bailey, D. L., Sawle, G. V. & Brooks, D. J. Measuring the rate of progression and estimating the preclinical period of Parkinson’ s disease with [18 F] dopa PET. J. Neurol. Neurosurg. Psychiatry 64, 314–319 (1998).
Eshuis, S. A., Maguire, R. P., Leenders, K. L., Jonkman, S. & Jager, P. L. Comparison of FP-CIT SPECT with F-DOPA PET in patients with de novo and advanced Parkinson’s disease. Eur. J. Nucl. Med. Mol. Imaging 33, 200–209 (2006). DOI: 10.1007/s00259-005-1904-y
Saari, L. et al. Dopamine transporter imaging does not predict the number of nigral neurons in Parkinson disease. Neurology 88, 1461–1467 (2017). DOI: 10.1212/WNL.0000000000003810
Reimão, S. et al. Substantia nigra neuromelanin-MR imaging differentiates essential tremor from Parkinson’s disease. Mov. Disord. 30, 953–959 (2015). DOI: 10.1002/mds.26182
Aquino, D. et al. Substantia nigra in Parkinson’s disease: a multimodal MRI comparison between early and advanced stages of the disease. Neurol. Sci. 35, 753–758 (2014). DOI: 10.1007/s10072-013-1595-2
Killilea, D. W., Wong, S. L., Cahaya, H. S., Atamna, H. & Ames, B. N. Iron accumulation during cellular senescence. Ann. N. Y. Acad. Sci. 1019, 365–367 (2004). DOI: 10.1196/annals.1297.063
Castellanos, G. et al. Automated neuromelanin imaging as a diagnostic biomarker for Parkinson’s disease. Mov. Disord. 30, 945–952 (2015). DOI: 10.1002/mds.26201
Antoniades, C. A. & Barker, R. The search for biomarkers in Parkinson’ s disease: a critical review. Expert Rev. Neurother. 8, 1841–1852 (2009). DOI: 10.1586/14737175.8.12.1841
Whone, A. L. et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: the REAL-PET study. Ann. Neurol. 54, 93–101 (2003). DOI: 10.1002/ana.10609
Brück, A. et al. Striatal subregional 6-[18 F]fluoro- L -dopa uptake in early Parkinson’s disease: a two-year follow-up study. Mov. Disord. 21, 958–963 (2006). DOI: 10.1002/mds.20855
Goetz, C. G. et al. Movement disorder society-sponsored revision of the unified Parkinson’s disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov. Disord. 23, 2129–2170 (2008). DOI: 10.1002/mds.22340
Herb, J. N. et al. Cortical implications of advancing age and disease duration in Parkinson’s disease patients with postural instability and gait dysfunction. J. Parkinsons. Dis. 6, 441–451 (2016). DOI: 10.3233/JPD-150753
Tomlinson, C. L. et al. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov. Disord. 25, 2649–2653 (2010). DOI: 10.1002/mds.23429
Weiskopf, N. et al. Quantitative multi-parameter mapping of R1, PD*, MT, and R2* at 3T: a multi-center validation. Front. Neurosci. 1–11 (2013). https://doi.org/10.3389/fnins.2013.00095.
Tabelow, K. et al. hMRI—a toolbox for quantitative MRI in neuroscience and clinical research. NeuroImage 194, 191–210 (2019). DOI: 10.1016/j.neuroimage.2019.01.029
Lutti, A., Hutton, C., Finsterbusch, J., Helms, G. & Weiskopf, N. Optimization and validation of methods for mapping of the radiofrequency transmit field at 3T. Magn. Reson. Med. 64, 229–238 (2010). DOI: 10.1002/mrm.22421
Lutti, A. et al. Robust and fast whole brain mapping of the RF transmit field B1 at 7T. PLoS ONE 7, 1–7 (2012). DOI: 10.1371/journal.pone.0032379
Priovoulos, N. et al. High-resolution in vivo imaging of human locus coeruleus by magnetization transfer MRI at 3T and 7T. Neuroimage 168, 427–436 (2018). DOI: 10.1016/j.neuroimage.2017.07.045
Fearnley, J. M. & Lees, A. J. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114, 2283–2301 (1991). DOI: 10.1093/brain/114.5.2283
Kordower, J. H. et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 136, 2419–2431 (2013). DOI: 10.1093/brain/awt192
Ashburner, J. & Friston, K. J. Unified segmentation. Neuroimage 26, 839–851 (2005). DOI: 10.1016/j.neuroimage.2005.02.018
Callaghan, M. F. et al. Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging. Neurobiol. Aging 35, 1862–1872 (2014). DOI: 10.1016/j.neurobiolaging.2014.02.008
Ashburner, J. A fast diffeomorphic image registration algorithm. Neuroimage 38, 95–113 (2007). DOI: 10.1016/j.neuroimage.2007.07.007
Draganski, B. et al. Regional specificity of MRI contrast parameter changes in normal ageing revealed by voxel-based quantification (VBQ). Neuroimage 55, 1423–1434 (2011). DOI: 10.1016/j.neuroimage.2011.01.052
Tzourio-Mazoyer, N. et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15, 273–289 (2002). DOI: 10.1006/nimg.2001.0978
Patlak, C. S. & Blasberg, R. G. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J. Cereb. Blood Flow Metab. 5, 584–590 (1985). DOI: 10.1038/jcbfm.1985.87
Haber, S. N. The place of dopamine in the cortico-basal ganglia circuit. Neuroscience 282, 248–257 (2014). DOI: 10.1016/j.neuroscience.2014.10.008
