Nigrosomal Iron Imaging in Parkinson's Disease

Parkinson Disease Clinical Trial

— N3iPD  

Official title:

Nigrosomal Iron Imaging in Parkinson's Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03022357
• Other study ID #: 16048
• Status: Recruiting
• Start date: June 2016
• Est. completion date: May 2019

Study information

• Verified date: January 2017
• Source: University of Nottingham
• Contact: Dorothee Auer
• Phone: 01158 231178
• Email: dorothee.auer[@]nottingham.ac.uk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Prospective observational study to compare sensitivity of 3T functional Magnetic Resonance Imaging (3T fMRI) at diagnosing Parkinson's Disease (PD) against the benchmark DaTScan diagnostic test and clinical diagnosis at follow up.

Description:

Idiopathic Parkinson's is characterized by loss of midbrain dopaminergic neurons preferentially affecting the nigrosomes of the pars compacta of the substantia nigra (SNpc). At the time of clinical diagnosis, an estimated 50-70% of the neurons of the SNpc are lost. Non-invasive imaging of cell loss in the nigrosomes containing the SNpc dopaminergic neurons would be clinically desirable for accurate diagnosis in clinically uncertain cases of parkinsonism, especially in the early stages of Parkinson's. Investigators recently discovered that high resolution susceptibility weighted MRI at 7T and 3T demonstrates iron related signal loss of the NS1 in Parkinson's. These studies proved the feasibility and potential of in vivo nigrosome MRI as new diagnostic tool for Parkinson's. Further support of and confidence in our novel diagnostic concept comes from similar observations by other research groups.

Project goals To establish whether nigrosome MRI is an alternative to DatScanTM in the diagnosis of early Parkinson's in patients with diagnostic uncertainty.

To establish whether nigrosomal iron predicts the severity of Parkinson's. As a secondary aim the investigators will study if nigrosomal iron load as determined by susceptometry correlates to disease severity (MDS-UPDRS).

TRIAL / STUDY OBJECTIVES AND PURPOSE

PURPOSE

• To establish whether nigrosome MRI is an alternative to DatScan in the diagnosis of early Parkinson's

• To establish whether nigrosomal iron predicts the severity of Parkinson's.

PRIMARY OBJECTIVE Validation of NS1 MRI as a qualitative diagnostic marker in early Parkinson's

• To investigate whether the presence or absence of the swallow tail on nigrosome MRI at 3T is as accurate as DatScan and at least 80% sensitive and 80% specific to predict the final clinical diagnosis of Parkinson's vs. other movement disorder in patients with indeterminate or atypical parkinsonian features.

Hypothesis 1: That the swallow tail sign is an accurate marker of early Parkinson's

SECONDARY OBJECTIVES Biomarker discovery based on quantitative nigrosome iron markers in Parkinson's • To investigate whether diagnostic performance of nigrosome MRI can be further improved through quantitative assessment of nigrosomal iron and combination with neuromelanin metrics.

Hypothesis 2: That nigrosomal iron metrics further improve the detection of early Parkinson's

• To assess how well disease severity can be predicted by iron content in the nigrosome and by a combination of iron content and the size of the neuromelanin-rich nigra volume.

Hypothesis 3: That nigrosomal iron metrics are closely associated with severity of early Parkinson's

The investigators will be recruiting 145 patients with diagnostic uncertainty of Parkinson's Disease. These patients will undergo a MRI and DATscans and will be clinically examined. They will then be followed-up (clinical examination) in 12 months, identifying if they can be confirmed as having Parkinson's Disease, in order to compare the sensitivity and specificity of nigrosome1 detected by MRI with DATScan, potentially allowing a non-invasive and much less expensive means of diagnosing Parkinson's Disease.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 145
• Est. completion date: May 2019
• Est. primary completion date: April 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 90 Years

Eligibility

Inclusion criteria:

• Ability to give informed consent

• Age > 21 to < 90 years

• Clinical symptoms suspicious for a diagnosis of Parkinson's disease but clinical uncertainty with regards to a definite diagnosis:

• Clinical symptoms not meeting all of the required UK brain bank diagnostic criteria for the diagnosis of PD

• Clinical features not typically associated with PD and therefore raising the possibility of a different type disorder/movement disorder

• Referred for a DatScan as part of the NHS clinical diagnostic workup to investigate a suspicion for a parkinsonian movement disorder type disease or referred for a research DatScan as part of this study for the diagnostic workup to investigate a suspicion for a parkinsonian movement disorder type disease.

Exclusion criteria:

• Participants with any known contraindication to MRI such as:

• Intracranial aneurysm clips

• Cardiac pacemakers and defibrillators

• Cochlear implants.

• MR-incompatible metal implant or tattoo

• Patients with a significant head tremor

• Claustrophobia

• Pregnant women

• Participants that are felt to be unfit for the MRI scan according to the judgement of medically qualified personnel, either on the research team, or the patient's clinical team. (eg. due to back pain, claustrophobia, acute sickness etc.) This includes patients with signs of impaired temperature regulation such as an extremely high fever.

• (only for those planned for research DatScan) Participants in which a DatScan nuclear medical study can't be performed due to

• Severe allergy to iodide compounds

• Thyroid gland dysfunction

Related Conditions & MeSH terms

• Parkinson Disease

Intervention

Other:
• Patient assessment
Clinical examination, Examination, Questionnaires

Radiation:
• DATScan
In small subgroup
• Orbital X-Ray
If foreign body in eye needs exclusion

Other:
• Magnetic Resonance Imaging (MRI)
MRI scanning of all subjects

Locations

Country	Name	City	State
United Kingdom	Royal Derby Hospital	Derby	Derbyshire
United Kingdom	Imperial College London	London
United Kingdom	University of Nottingham	Nottingham

Sponsors (3)

Lead Sponsor	Collaborator
University of Nottingham	Michael J. Fox Foundation for Parkinson's Research, National Institute for Health Research, United Kingdom

Country where clinical trial is conducted

United Kingdom, 

References & Publications (19)

Baudrexel S, Nürnberger L, Rüb U, Seifried C, Klein JC, Deller T, Steinmetz H, Deichmann R, Hilker R. Quantitative mapping of T1 and T2* discloses nigral and brainstem pathology in early Parkinson's disease. Neuroimage. 2010 Jun;51(2):512-20. doi: 10.1016/j.neuroimage.2010.03.005. Epub 2010 Mar 6. — View Citation

Beam CA. Strategies for improving power in diagnostic radiology research. AJR Am J Roentgenol. 1992 Sep;159(3):631-7. — View Citation

Blazejewska AI, Schwarz ST, Pitiot A, Stephenson MC, Lowe J, Bajaj N, Bowtell RW, Auer DP, Gowland PA. Visualization of nigrosome 1 and its loss in PD: pathoanatomical correlation and in vivo 7 T MRI. Neurology. 2013 Aug 6;81(6):534-40. doi: 10.1212/WNL.0b013e31829e6fd2. Epub 2013 Jul 10. — View Citation

Cosottini M, Frosini D, Pesaresi I, Costagli M, Biagi L, Ceravolo R, Bonuccelli U, Tosetti M. MR imaging of the substantia nigra at 7 T enables diagnosis of Parkinson disease. Radiology. 2014 Jun;271(3):831-8. doi: 10.1148/radiol.14131448. Epub 2014 Feb 26. — View Citation

Cosottini M, Frosini D, Pesaresi I, Donatelli G, Cecchi P, Costagli M, Biagi L, Ceravolo R, Bonuccelli U, Tosetti M. Comparison of 3T and 7T susceptibility-weighted angiography of the substantia nigra in diagnosing Parkinson disease. AJNR Am J Neuroradiol. 2015 Mar;36(3):461-6. doi: 10.3174/ajnr.A4158. Epub 2014 Nov 6. — View Citation

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 Aug;122 ( Pt 8):1421-36. — View Citation

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 Aug;122 ( Pt 8):1437-48. — View Citation

Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain. 1991 Oct;114 ( Pt 5):2283-301. — View Citation

Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain. 2002 Apr;125(Pt 4):861-70. — View Citation

Hughes 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 Mar;55(3):181-4. — View Citation

Kwon DH, Kim JM, Oh SH, Jeong HJ, Park SY, Oh ES, Chi JG, Kim YB, Jeon BS, Cho ZH. Seven-Tesla magnetic resonance images of the substantia nigra in Parkinson disease. Ann Neurol. 2012 Feb;71(2):267-77. doi: 10.1002/ana.22592. — View Citation

Piccini P, Whone A. Functional brain imaging in the differential diagnosis of Parkinson's disease. Lancet Neurol. 2004 May;3(5):284-90. Review. — View Citation

Pirker W, Asenbaum S, Bencsits G, Prayer D, Gerschlager W, Deecke L, Brücke T. [123I]beta-CIT SPECT in multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Mov Disord. 2000 Nov;15(6):1158-67. — View Citation

Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism--a prospective study. Can J Neurol Sci. 1991 Aug;18(3):275-8. — View Citation

Reiter E, Mueller C, Pinter B, Krismer F, Scherfler C, Esterhammer R, Kremser C, Schocke M, Wenning GK, Poewe W, Seppi K. Dorsolateral nigral hyperintensity on 3.0T susceptibility-weighted imaging in neurodegenerative Parkinsonism. Mov Disord. 2015 Jul;30(8):1068-76. doi: 10.1002/mds.26171. Epub 2015 Mar 15. — View Citation

Schuff N. Potential role of high-field MRI for studies in Parkinson's disease. Mov Disord. 2009;24 Suppl 2:S684-90. doi: 10.1002/mds.22647. Review. — View Citation

Schwarz ST, Afzal M, Morgan PS, Bajaj N, Gowland PA, Auer DP. The 'swallow tail' appearance of the healthy nigrosome - a new accurate test of Parkinson's disease: a case-control and retrospective cross-sectional MRI study at 3T. PLoS One. 2014 Apr 7;9(4):e93814. doi: 10.1371/journal.pone.0093814. eCollection 2014. — View Citation

Wallis LI, Paley MN, Graham JM, Grünewald RA, Wignall EL, Joy HM, Griffiths PD. MRI assessment of basal ganglia iron deposition in Parkinson's disease. J Magn Reson Imaging. 2008 Nov;28(5):1061-7. doi: 10.1002/jmri.21563. — View Citation

Zhang W, Sun SG, Jiang YH, Qiao X, Sun X, Wu Y. Determination of brain iron content in patients with Parkinson's disease using magnetic susceptibility imaging. Neurosci Bull. 2009 Dec;25(6):353-60. doi: 10.1007/s12264-009-0225-8. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Presence or absence of "swallow tail" on nigrosome MRI at 3T	Does absence of "swallow tail" on nigrosome MRI at 3T correlate with final diagnosis of Parkinson's Disease 12 months after initial presentation of clinically uncertain diagnosis? Is this correlation as accurate as that of DatScan? Is nigrosome MRI at 3T at least 80% sensitive and 80% specific to predict the final clinical diagnosis of Parkinson's disease vs. other movement disorders in patients with indeterminate or atypical parkinsonian features? Is the "swallow tail" and accurate marker of early Parkinson's disease.	12 months

External Links

•   NICE Guideline (UK). Diagnosing Parkinson's disease. 2006 [cited 2015 Jul 31]