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BACKGROUND

  • Parkinson's Disease (PD) is a progressive brain disease that causes a variety of difficult and disabling symptoms. These can include tremor, problems walking, sleep disorders, cognitive decline and dementia.

 

  • About 1% of adults over age 65 have PD.

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  • Despite numerous attempts, no treatments have succeeded in slowing down or stopping PD. Biomarkers are quantifiable features of disease biology. PD biomarkers may be useful to improve clinical trial designs. They may help with subject selection and outcome measurement. They may also be useful for patients and doctors in the clinic.

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  • PD neuroimaging biomarkers for clinical and research uses are an important unmet need​.

SNc

LC

  • Degeneration of pigmented catecholamine neurons in substantia nigra pars compacta (SNc) and locus coeruleus (LC) are hallmark pathologies in PD. [1,2]

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  • First reported in 2006, neuromelanin-sensitive MRI (NM-MRI) is a rapidly emerging imaging modality sensitive to neuromelanin in SNc and LC. [3]

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  • Technical challenges have limited its translational application due to:

    • problems with excessive energy delivery (resulting in aborted scans)

    • a need for improved signal to noise characteristics, and

    • a need for an automated image processing method. [3,4]

NEUROMELANIN-SENSITIVE MRI APPROACH

  • NM-MRI contrast is generated by magnetization transfer contrast (MTC) effects, likely involving melanin-iron complexes. [5,6]

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  • We use an explicit MTC approach that delivers less energy and has improved contrast-to-noise ratio as compared to earlier NM-MRI methods. [4] Previous methods have relied upon incidental MTC that results from multi-slice imaging. [7] Incidental MTC delivers large amounts of energy and contrast may vary across subjects, resulting in an inconsistent data set. [3,8]

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  • In 2014, we reported a novel NM-MRI approach to address the challenges mentioned above. [4] We used a reduced flip-angle MT pulse to deliver less energy, preventing aborted scans. We observed improved contrast-to-noise ratio with the explicit MTC approach as compared to the incidental MTC approach.

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  • We improved image processing with steps to remove motion artifacts (especially important in LC) and made processing fully automated and reproducible.

METHOD FOR SEGMENTING SNc [4]
Segmenting the Substantia Nigra Pars Compacta

(A) Image showing​ hyperintense NM-MRI contrast in SNc.

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(B1) The signal intensity mean and standard deviation were determined for reference regions in the cerebral peduncles.

(B2) The signal intensities were found to be approximately normally distributed.

(B3) Hyperintense SNc voxels, at least three standard deviations greater in intensity than the mean intensity in the reference region, were identified as SNc.

(B4) Thresholding was restricted to the anatomic location of SNc using a previously reported probabilistic standard space mask dilated for this purpose. Segmented left (yellow) and right (red) SNcs.

 

**LC segmentation is carried out using a similar approach.

REPRODUCIBILITY

  • Establishing scan-rescan reproducibility and replication in multiple cohorts are crucial steps in biomarker development.

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  • In 2017, we reported the very high scan-rescan reproducibility of the NM-MRI method, with an intraclass correlation coefficient of 0.94 for SNc volume and 0.96 for LC volume. [9]

 

**We also detected PD-associated SNc and LC volume loss in separate cohorts on different scanner models. [10]

Reproducibility of LC and SNc Imaging
NM-MRI SELECTION OF THE SNc REGION OF INTEREST

  • ​Using NM-MRI contrast to define the SNc enables accurate, reproducible selection of this region of interest (ROI) with an automated image processing approach. [8,11]

 

  • NM-MRI data from a group of controls (n=31) was used to develop a standard space probabilistic population mask for SNc. [12]

  • ​Our group showed that NM loss and iron accumulation are mostly non-overlapping. [5]

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  • The nigral NM-MRI contrast volume is spatially located within SNc. [13]

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  • Iron accumulation is spatially located within substantia nigra pars reticulata (SNr). [5]

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  • The spatial relationship between the NM-MRI nigral volume (SNc) and the iron-sensitive MRI nigral volume (SNr) is shown in the graphic to the right. 

NM-MRI/IRON CONTRAST OVERLAP: 
A CANDIDATE PD BIOMARKER [14]

  • In healthy controls, the neuromelanin-sensitive and iron-sensitive MRI contrast volumes overlap by about 10%. This reflects the relatively high iron content of SNr as compared to SNc in healthy individuals.

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  • In PD iron accumulation occurs in SNc. We observed that the overlap between the neuromelanin-sensitive and iron-sensitive contrast volumes is greatly increased in PD. This difference is highly significant with p< 10-15  

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  • Notably, the location of the overlap region is the lateral-ventral portion of SNc. This is the nigral subregion most profoundly damaged by PD. 

 

  • We developed an additional probablistic population mask for the overlap region in PD to use as an ROI selection tool.

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  • Both the overlap percentage and measures of iron within the overlap region represent promising candidate PD biomarkers.

NM-sensitive and iron-sensitive MRI contrast overlap in SNc. The colored regions are the NM-sensitive contrast region, i.e. SNc. The red/yellow colored regions are the areas of contrast overlap between iron-sensitive and NM-sensitive contrast in SNc. The contrast overlap region is significantly increased in PD. 

References

1. Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991;114:2283 -1. Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991;114:2283 - 2301.

2. Zarow C, Lyness SA, Mortimer JA, Chui HC. Neuronal Loss Is Greater in the Locus Coeruleus Than Nucleus Basalis and Substantia Nigra in Alzheimer and Parkinson Diseases. Arch Neurol 2003;60:337-341.

3. 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. Mov Disord 2011;26:1633-1638.

4. Chen X, Huddleston DE, Langley J, et al. Simultaneous imaging of locus coeruleus and substantia nigra with a quantitative neuromelanin MRI approach. Magnetic resonance imaging 2014.

5. Langley J, Huddleston DE, Chen X, Sedlacik J, Zachariah N, Hu X. A multicontrast approach for comprehensive imaging of substantia nigra. Neuroimage 2015;112:7-13.  

6. Trujillo P, Summers PE, Ferrari E, et al. Contrast mechanisms associated with neuromelanin-MRI. Magn Reson Med 2016. doi: 10.1002/mrm.26584 [Epub]

7. Dixon WT, Engels H, Castillo M, Sardashti M. Incidental magnetization transfer contrast in standard multislice imaging. Magnetic resonance imaging. 1990;8(4):417-22. Epub 1990/01/01. PubMed PMID: 2392030.

8. Huddleston D, Langley J, Dusek P, He N, Faraco C, Crosson B, Factor S, Hu X. Imaging Parkinsonian Pathology in Substantia Nigra with MRI. Curr Radiol Rep. 2018;6(15):1-13.

9. Langley J, Huddleston DE, Liu CJ, Hu X. Reproducibility of locus coeruleus and substantia nigra imaging with neuromelanin sensitive MRI. MAGMA 2017;30:121-125.

10. Huddleston D, Langley J, McMurray R, De Louis F, Factor S, XP H. Advanced Neuromelanin Sensitive MRI Measures Detect Parkinson's Disease Effects in Catecholamine Nuclei: Discovery and Validation in Separate Cohorts. Neurology. 2017;88(16 Supplement): P1. 076.

11. Langley J, Huddleston DE, Merritt M, et al. Diffusion tensor imaging of the substantia nigra in Parkinson's disease revisited. Human brain mapping 2016;37:2547-2556.

12. Langley J*, He N*, Huddleston DE*, Chen S, Yan F, Crosson B, Factor S, Hu X. Reproducible detection of nigral iron deposition in 2 Parkinson’s disease cohorts. Movement Disorders. (2019) March;34(3):416-419. *equal contributions--shared first-authorship.

13. Kitao S, Matsusue E, Fujii S, Miyoshi F, Kaminou T, Kato S, Ito H, Ogawa T. Correlation between pathology and neuromelanin MR imaging in Parkinson's disease and dementia with Lewy bodies. Neuroradiology. 2013;55(8):947-53. doi: 10.1007/s00234-013-1199-9. PubMed PMID: 23673875.

14. Langley J, Huddleston DE, Sedlacik J, Boelmans K, Hu XP. Parkinson's disease-related increase of T2*-weighted hypointensity in substantia nigra pars compacta. Mov Disord. 2017;32(3):441-9. doi: 10.1002/mds.26883. PubMed PMID: 28004859.

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