Visualization of nigrosome 1 and its loss in PD
Pathoanatomical correlation and in vivo 7 T MRI
Abstract
Objective:
This study assessed whether high-resolution 7 T MRI allowed direct in vivo visualization of nigrosomes, substructures of the substantia nigra pars compacta (SNpc) undergoing the greatest and earliest dopaminergic cell loss in Parkinson disease (PD), and whether any disease-specific changes could be detected in patients with PD.
Methods:
Postmortem (PM) midbrains, 2 from healthy controls (HCs) and 1 from a patient with PD, were scanned with high-resolution T2*-weighted MRI scans, sectioned, and stained for iron and neuromelanin (Perl), TH, and calbindin. To confirm the identification of nigrosomes in vivo on 7 T T2*-weighted scans, we assessed colocalization with neuromelanin-sensitive T1-weighted scans. We then assessed the ability to depict PD pathology on in vivo T2*-weighted scans by comparing data from 10 patients with PD and 8 age- and sex-matched HCs.
Results:
A hyperintense, ovoid area within the dorsolateral border of the otherwise hypointense SNpc was identified in the HC brains on in vivo and PM T2*-weighted MRI. Location, size, shape, and staining characteristics conform to nigrosome 1. Blinded assessment by 2 neuroradiologists showed consistent bilateral absence of this nigrosome feature in all 10 patients with PD, and bilateral presence in 7/8 HC.
Conclusions:
In vivo and PM MRI with histologic correlation demonstrates that high-resolution 7 T MRI can directly visualize nigrosome 1. The absence of nigrosome 1 in the SNpc on MRI scans might prove useful in developing a neuroimaging diagnostic test for PD.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
REFERENCES
1.
Lehéricy S, Sharman MA, Santos CLD, Paquin R, Gallea C. Magnetic resonance imaging of the substantia nigra in Parkinson's disease. Mov Disord 2012;27:822–830.
2.
Auer DP. In vivo imaging markers of neurodegeneration of the substantia nigra. Exp Gerontol 2009;44:4–9.
3.
Massey LA, Yousry TA. Anatomy of the substantia nigra and subthalamic nucleus on MR imaging. Neuroimaging Clin N Am 2010;20:7–27.
4.
Haines DE. Fundamental Neuroscience for Basic and Clinical Applications. Philadelphia: Churchill Livingstone Elsevier; 2006.
5.
Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain I: nigrosomes and the nigral matrix, a compartmental organization based on calbindin D 28K immunohistochemistry. Brain 1999;122:1421–1436.
6.
Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain II: patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain 1999;122:1437–1448.
7.
Baron S, Wood D. Rec. 601—the origins of the 4:2:2 DTV standard. In: EBU Technical Review. Grand-Saconnex, Switzerland: European Broadcasting Union; 2005:1–11.
8.
Ruifrok AC, Johnston DA. Quantification of histochemical staining by color deconvolution. Anal Quant Cytol Histol 2001;23:291–299.
9.
Sasaki M, Shibata E, Kudo K, Tohyama K. Neuromelanin-sensitive MRI. Clin Neuroradiol 2008;18:147–153.
10.
Schwarz ST, Rittman T, Gontu V, Morgan PS, Bajaj N, Auer DP. T1-weighted MRI shows stage-dependent substantia nigra signal loss in Parkinson's disease. Move Disord 2011;26:1633–1638.
11.
Huges AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;5:181–184.
12.
Kwon DH, Kim JM, Oh SH, et al. Seven-Tesla magnetic resonance images of the substantia nigra in Parkinson disease. Ann Neurol 2012;71:267–277.
13.
Berg D. Hyperechogenicity of the substantia nigra: pitfalls in assessment and specificity for Parkinson's disease. J Neural Transm 2011;118:453–461.
14.
Griffiths PD, Dobson BR, Jones GR, Clarke DT. Iron in the basal ganglia in Parkinson's disease: an in vitro study using extended X-ray absorption fine structure and cryo-electron microscopy. Brain 1999;122:667–673.
15.
Sofic E, Riederer P, Heinsen H, et al. Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 1988;74:199–205.
16.
Friedman A, Galazka-Friedman J, Koziorowski D. Iron as a cause of Parkinson disease: a myth or a well established hypothesis? Parkinsonism Relat Disord 2009;15(suppl 3):212–214.
17.
Haacke EM, Cheng NYC, House MJ, et al. Imaging iron stores in the brain using magnetic resonance imaging. Magn Reson Imaging 2005;23:1–25.
18.
Minati L, Grisoli M, Carella F, Simone TD, Bruzzone MG, Savoiardo M. Imaging degeneration of the substantia nigra in Parkinson disease with inversion-recovery. AJNR Am J Neuroradiol 2007;28:309–313.
19.
Lotfipour AK, Wharton S, Schwarz ST, et al. High resolution magnetic susceptibility mapping of the substantia nigra in Parkinson's disease. J Magn Reson Imaging 2012;35:48–55.
20.
Gore JC, Kang YS, Schulz RJ. Measurement of radiation dose distributions by nuclear magnetic resonance (NMR) imaging. Phys Med Biol 1984;29:1189–1197.
21.
Scharg M, Dickson A, Jiffry A, Kirsch D, Vinters HV, Kirsh W. The effect of formalin fixation on the levels of brain transition metals in archived samples. Biometals 2010;23:1123–1127.
22.
Gellein K, Flaten TP, Erikson KM, Aschner M, Syversen T. Leaching of trace elements from biological tissue by formalin fixation. Biol Trace Elem Res 2008;121:221–225.
23.
Maclaren J, Lee KJ, Luengviriya C, Speck O, Zaitsev M. Combined prospective and retrospective motion correction to relax navigator requirements. Magn Reson Med 2011;65:1724–1732.
24.
Ordidge RJ, Gorell JM, Deniau JC, Knight RA, Helpern JA. Assessment of relative brain iron concentrations using T2-weighted and T2*-weighted MRI at 3 Tesla. Magn Reson Med 1994;32:335–341.
25.
Cho Z, Kim Y, Han J, et al. New brain atlas: mapping the human brain in vivo with 7.0 T MRI and comparison with Postmortem histology: will these images change modern medicine? Int J Imaging Syst Technol 2008;18:2–8.
26.
Cho Z, Oh S, Kim J. Direct Visualization of Parkinson's disease by in vivo human brain imaging using 7.0T magnetic resonance imaging. Move Disord 2011;26:713–755.
27.
Menke RA, Scholz J, Miller KL, et al. MRI characteristics of the substantia nigra in Parkinson's disease: a combined quantitative T1 and DTI study. Neuroimage 2009;47:435–441.
28.
Menke RA, Jbabdi S, Miller KL, Matthews PM, Zarei M. Connectivity-based segmentation of the substantia nigra in human and its implications in Parkinson's disease. Neuroimage 2010;52:1175–1180.
29.
Eapen M, Zald DH, Gatenby JC, Ding Z, Gore JC. Using high-resolution MR imaging at 7T to evaluate the anatomy of the midbrain. AJNR Am J Neuroradiol 2011;32:688–694.
30.
Mai JK, George P. The Human Nervous System, 2nd ed. Philadelphia: Elsevier; 2004.
31.
Bagnato F, Hametner S, Yao B, et al. Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla. Brain 2011;134:3602–3615.
Information & Authors
Information
Published In
Copyright
© 2013 American Academy of Neurology.
Publication History
Received: January 11, 2013
Accepted: April 17, 2013
Published online: July 10, 2013
Published in print: August 6, 2013
Disclosure
The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Study Funding
Supported by Medical Research Council and Engineering and Physical Sciences Research Council (grant number: RA27EY).
Authors
Author Contributions
Anna I. Blazejewska: study design, literature search, data collection, data analysis, interpretation of results, figures, and writing the paper. Stefan T. Shwarz: patient recruitment, interpretation of results, and writing the paper. Alain Pitiot: data analysis. Mary C. Stephenson: data collection. James Lowe: histology and interpretation of results. Nin Bajaj: patient recruitment and interpretation of results. Dorothee P. Auer: study design, patient recruitment, interpretation of results, and writing the paper. Richard W. Bowtell: interpretation of results. Penny A. Gowland: study design, data collection, data analysis, interpretation of results, and writing the paper. Guarantor: Penny A. Gowland.
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
- Improved diagnostic performance of susceptibility-weighted imaging with compressed sensing-sensitivity encoding and neuromelanin-sensitive MRI for Parkinson's disease and atypical Parkinsonism, Clinical Radiology, 79, 1, (e102-e111), (2024).https://doi.org/10.1016/j.crad.2023.09.019
- Molecular Imaging of Parkinson’s Disease, Molecular Imaging and Therapy, (1-13), (2023).https://doi.org/10.36255/molecular-imaging-of-parkinsons-disease
- Quantitative iron–neuromelanin MRI associates with motor severity in Parkinson's disease and matches radiological disease classification, Frontiers in Aging Neuroscience, 15, (2023).https://doi.org/10.3389/fnagi.2023.1287917
- The role of magnetic resonance imaging in the diff erential diagnosis of Parkinson’s disease, Russian neurological journal, 28, 1, (5-12), (2023).https://doi.org/10.30629/26587947-2023-28-1-5-12
- In vivo detection of substantia nigra and locus coeruleus volume loss in Parkinson’s disease using neuromelanin-sensitive MRI: Replication in two cohorts, PLOS ONE, 18, 4, (e0282684), (2023).https://doi.org/10.1371/journal.pone.0282684
- Imaging in Movement Disorders, CONTINUUM: Lifelong Learning in Neurology, 29, 1, (194-218), (2023).https://doi.org/10.1212/CON.0000000000001210
- Brainstem anatomy with 7-T MRI: in vivo assessment and ex vivo comparison, European Radiology Experimental, 7, 1, (2023).https://doi.org/10.1186/s41747-023-00389-y
- The applied value in brain gray matter nuclei of patients with early-stage Parkinson’s disease : a study based on multiple magnetic resonance imaging techniques, Head & Face Medicine, 19, 1, (2023).https://doi.org/10.1186/s13005-023-00371-4
- Structural and Molecular Imaging for Clinically Uncertain Parkinsonism, Seminars in Neurology, 43, 01, (095-105), (2023).https://doi.org/10.1055/s-0043-1764228
- Diagnosing Parkinson's disease by combining neuromelanin and iron imaging features using an automated midbrain template approach, NeuroImage, 266, (119814), (2023).https://doi.org/10.1016/j.neuroimage.2022.119814
- See more
Loading...
View Options
Get Access
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
Purchase this article to get full access to it.
Blazejewska et al. [1] identified a hyperintense, ovoid area within the dorsolateral border of the otherwise hypointense pars compacta of the substantia nigra (SNc) in healthy controls (HC) and the absence of this MRI feature [2] in PD patients using T2*-weighted 7T-MRI. Moreover, the post- mortem 7T-MRI with histopathological correlations suggested that this MRI feature corresponded to nigrosome 1. We studied this MRI feature in consecutively recruited HC and PD patients [3] (n: HC 16, PD 53; age, mean+/-SD: HC 67+/-8 years, PD 54+/-10 years; proportion of females: HC 68%, PD 28%; disease duration, mean+/-SD:8+/-4 years) using SWI-weighted MRI at 3T (Siemens Verio MR scanner). Datasets of two HC and 18 PD patients were not of diagnostic quality due to patient motion. In the remaining patients, presence of dorsolateral hyperintensity within the otherwise hypointense SNc was identified in 14/14 HC and 5/35 PD patients. Absence of this MRI feature resulted in 85.7% sensitivity and 100% specificity to detect PD. We suggest that this MRI feature reported at 7T-MRI using T2*-weighted sequences [1] can also be detected at 3T using SWI sequences and that absence of this MRI feature might have potential for diagnosing PD.
1. Blazejewska AI, Schwarz ST, Pitiot A, et al. Visualization of nigrosome 1 and its loss in PD: pathoanatomical correlation and in vivo 7 T MRI. Neurology 2013;81:534-540.
2. Kwon DH, Kim JM, Oh SH, et al. Seven-Tesla magnetic resonance images of the substantia nigra in Parkinson disease. Annals of neurology 2012;71:267-277.
3. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. Journal of neurology, neurosurgery, and psychiatry 1992;55:181-184.
For disclosures, please contact the editorial office at [email protected].
We thank Mueller et al. for their comments on our article concerning the application of 7T T2* MRI for PD diagnostics. [1] We were delighted to read about their successful use of 3T SWI for detection of nigrosome 1 absence in the substantia nigra of PD patients. We also studied the application of 3T susceptibility weighted imaging in PD cohorts as a fast and easily applicable diagnostic tool. Early results indicate a sensitivity of 89-95 % and a specificity of 91% of nigrosome 1 detection using 3T MRI, [2] which are similar to results from the 7T MRI study. Interestingly, our rate of non- diagnostic scans was much lower compared with the 29% reported by Mueller et al. Their study in 14 controls and 35 PD patients (out of 69 scanned) needs replication with a stricter protocol and in a larger cohort including atypical parkinsonism. Translation of the discovery made at 7T to 3T is particular promising due to the general availability of 3T scanners and the lack of post- processing required for nigrosome detection. 3T may be a potential viable alternative to the more expensive, nuclear medical techniques currently licensed.
1. Blazejewska AI, Schwarz ST, Pitiot A, et al. Visualization of nigrosome 1 and its loss in PD: pathoanatomical correlation and in vivo 7 T MRI. Neurology 2013;81:534-540.
2. Schwarz ST, Afzal M, Morgan PS, Bajaj N, Auer DP. Nigrosome imaging with T2*-weighted 3T MRI as a diagnostic marker of Parkinson's disease: a case-control and cross-sectional study of diagnostic accuracy, The Lancet, Special edition February 2014, Spring Meeting for Clinician Scientists in Training, Poster session 83, Poster 102, in print.
For disclosures, please contact the editorial office at [email protected].