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
et al. (2014) 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 9(4): e93814. doi:10.1371/journal.pone.0093814
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
Stefan T. Schwarz 0
Mohammed Afzal 0
Paul S. Morgan 0
Nin Bajaj 0
Penny A. Gowland 0
Dorothee P. Auer 0
Ashley I. Bush, University of Melbourne, Australia
0 1 Radiological Sciences, Division of Clinical Neurosciences, School of Medicine, University of Nottingham , Nottingham , United Kingdom , 2 Department of Medicine, Nottingham University Hospitals NHS Trust , Nottingham , United Kingdom , 3 Medical Physics , Nottingham University Hospitals NHS Trust , Nottingham , United Kingdom , 4 Department of Neurology, Nottingham University Hospitals NHS Trust , Nottingham , United Kingdom , 5 Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy , Nottingham , United Kingdom
There is no well-established in vivo marker of nigral degeneration in Parkinson's disease (PD). An ideal imaging marker would directly mirror the loss of substantia nigra dopaminergic neurones, which is most prominent in sub-regions called nigrosomes. High-resolution, iron-sensitive, magnetic resonance imaging (MRI) at 7T allows direct nigrosome-1 visualisation in healthy people but not in PD. Here, we investigated the feasibility of nigrosome-1 detection using 3T - susceptibilityweighted (SWI) MRI and the diagnostic accuracy that can be achieved for diagnosing PD in a clinical population. 114 highresolution 3T - SWI-scans were reviewed consisting of a prospective case-control study in 19 subjects (10 PD, 9 controls) and a retrospective cross-sectional study in 95 consecutive patients undergoing routine clinical SWI-scans (.50 years, 9 PD, 81 non-PD, 5 non-diagnostic studies excluded). Two raters independently classified subjects into PD and non-PD according to absence or presence of nigrosome-1, followed by consensus reading. Diagnostic accuracy was assessed against clinical diagnosis as gold standard. Absolute inter- and intra-rater agreement was $94% (kappa$0.82, p,0.001). In the prospective study 8/9 control and 8/10 PD; and in the retrospective study 77/81 non-PD and all 9 PD subjects were correctly classified. Diagnostic accuracy of the retrospective cohort was: sensitivity 100%, specificity 95%, NPV 1, PPV 0.69 and accuracy 96% which dropped to 91% when including non-diagnostic scans ('intent to diagnose'). The healthy nigrosome-1 can be readily depicted on high-resolution 3T - SWI giving rise to a 'swallow tail' appearance of the dorsolateral substantia nigra, and this feature is lost in PD. Visual radiological assessment yielded a high diagnostic accuracy for PD vs. an unselected clinical control population. Assessing the substantia nigra on SWI for the typical 'swallow tail' appearance has potential to become a new and easy applicable 3T MRI diagnostic tool for nigral degeneration in PD.
Funding: The prospective substudy was co-funded by Special Trustees for Nottingham University Hospital (Grant Ref: STR 82/04/N), the Sarah Matheson Trust
(now Multiple System Atrophy Trust founded by Sarah Matheson, No reference number given (http://www.msatrust.org.uk), and the Medical Research Council
(Grant Ref: G0901321). The author S.T. Schwarz is funded by the National Institute for Health Research UK (Academic Clinical Lectureship). The funders had no role
in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Parkinsons disease (PD) is a progressive neurodegenerative
disorder resulting in characteristic motor and non-motor
symptoms. The motor features form the basis of the clinical diagnosis
and are embedded in the UK-Brain bank criteria for diagnosing
PD . Establishing the clinical diagnosis can be challenging in
early or tremor dominant cases. The reported diagnostic error
rates are 4-15% in clinical trials and up to 25% in community
studies . Ioflupane (123I) single photon emission computer
tomography (SPECT) has proved useful in establishing presynaptic
dopaminergic loss in difficult diagnostic cases  using dopamine
transporter imaging of the striatum as a surrogate marker for
nigral dopaminergic cell loss. This technique has been recently
approved by the American Food and Drug Administration for
diagnostic purposes in PD (DaTscan, approved January 2011).
However, these types of scans are expensive, involve low dose
radiation and are only available in specialised centres. Correlation
with disease progression is limited. Furthermore, DaTscan is not
currently licensed for differentiation of some of the parkinsonian
conditions that can be mistaken for PD, including progressive
supranuclear gaze palsy parkinsonian variant (PSP-P) and multiple
system atrophy type P (MSA-P) .
Research into alternative biomarkers of PD in recent years has
demonstrated a range of genetic, biochemical and also imaging
techniques with varying ranges of accuracy, repeatability and
reliability . However, to date, none of the investigated methods
demonstrate the required accuracy and ease of use to allow
translation to standard clinical practice and DaTscan remains the
only licensed PD diagnostic tool.
The neurons of the pars compacta of the substantia nigra
(SNPC) are affected early in PD, with loss of 60-80% of neurons
described before manifestation of motor symptoms .
Nigrosomes represent small clusters of dopaminergic cells within the
healthy substantia nigra exhibiting calbindin D28K negativity on
immunohistochemical staining . The largest nigrosome of the
five described nigrosomes is labelled nigrosome-1 and positioned
in the caudal and medio-lateral SN. It contains the biggest
proportion of neurons which are most commonly affected by PD
. Despite the small physical size of only a few mm, both the
healthy nigrosome-1 and PD induced pathological change within
nigrosome-1 can be demonstrated with high resolution T2*/SWI
(HR-SWI) weighted magnetic resonance imaging (MRI) at
ultrahigh magnetic field strengths of 7T .
Translating this technique to 3T - MRI platforms in order to
support the diagnosis of PD would be highly desirable, as MRI at
3T is widely available and much less expensive than licensed
nuclear medical techniques. It additionally offers the opportunity
for combining diagnostic confirmation of nigral degeneration in
PD with promising MRI techniques for differentiating other
parkinsonian conditions such as PSP-P, MSA-P and vascular
parkinsonism [12,13]. In this combined prospective and
retrospective study including 114 SWI scans at 3T, we investigated the
feasibility of HR-SWI MRI at 3T to depict PD related signal loss
within nigrosome-1 and the diagnostic accuracy that can be
achieved in a clinical population (50+ years of age).
Prospective case-control study
This study was part of a multimodal MRI characterization of
the substantia nigra in patients with PD that was approved by the
local Research Committee (North Nottinghamshire Research
Ethics Committee, UK, reference 05/Q2402/87) and the Trust
Research and Development Department (Nottingham University
Hospitals NHS Trust) [14,15]. Written informed consent was
obtained from all participants in person before enrolment in the
study. Assessment of capacity and obtaining of consent was
performed by a neurology consultant of the University of
Nottingham Hospitals NHS trust. Ten patients fulfilling the UK
Brain Bank criteria for PD were recruited from movement
disorders clinics at two local National Health Service trusts. Nine
age-matched controls were recruited from spouses and friends. All
subjects underwent the Addenbrookes Cognitive Examination
(ACE) test battery  and had to have a score .80 for inclusion.
All participants had Mini-Mental State examination scores $27
). Disease severity was recorded using the UPDRS  and
Hoehn and Yahr clinical rating scales for PD . The patients
were sub-categorized into tremor dominant cases (TDPD) and
postural instability and gait disturbance patients (PIGD) according
to previously published assessment methods . Patients were
assessed and scanned whilst medicated.
MR imaging was performed at 3T (Achieva scanner, Philips
Medical Systems, Best, Netherlands) with a standard eight-channel
head coil. The image acquisition was performed using a HR-SWI
weighted sequence with 3D acquisition using a gradient echo
planar imaging sequence (FEEPI, TR/TE 60/30, echo train
length 5, Flip angle 19u, number of slices: 70, voxel size
Figure 1. Substantia nigra anatomy on 3T - SWI MRI. Demonstrated is a 3T - SWI axial slice just at the level of nigrosome-1 with magnification
of the midbrain structures and a sketch outlining relevant anatomical structures: 1 red nucleus, 2 midbrain tegmentum, 3 aqueduct, 4 periaqueductal
grey, 5 medial leminiscus, 6 nigrosome-1, 7 substantia nigra, 8 cerebral peduncle, 9 mammillary body, 10 inter-peduncular fossa, 11 optic radiation, 12
3rd ventricle, 13 temporal lobe, 14 cerebellum, 15 frontal lobe.
0.5560.5560.7 mm, scan duration: 4 minutes 26 seconds, only
magnitude image used). The orientation of the axial slices was
individually aligned parallel to the splenium and genu line of the
corpus callosum. The magnitude images were reviewed in multiple
planes using 3D slicer or a locally developed image viewing and
analysis software (NeuRoi, http://www.nottingham.ac.uk/
research/groups/clinicalneurology/neuroi.aspx) on standard
PCLCD flat screen displays.
Retrospective cross-sectional study
The retrospective study was performed by clinical personnel as
part of an institutionally approved service evaluation/audit
(Department of Radiology, Nottingham University Hospitals
NHS Trust) to assess the potential of improved patient care after
introduction of a HR-SWI sequence into routine MRI protocols.
As per local guideline approval was obtained from the Directorate
Clinical Director and Head of Neuroradiology Service who in
accordance of the Caldicott guardian waived informed consent for
the retrospective data collection and review. We also obtained
guidance by a chair holder of the Research Ethics Committee
(Nottingham Research Ethics Service, Health Research Authority,
UK) who confirmed that there is no requirement for a formal
Research Ethics Committee review.
The imaging data were reviewed on local radiology reporting
workstations (AGFA IMPAX 22.214.171.1247, 3D reconstructions:
AGFA IMPAX Volume Viewing 2.2, Clinapps 4.2.31, AGFA
Healthcare, Mortsel, Belgium). Patient clinical data were collected
by retrospectively reviewing patient clinical information
(Nottingham information system NOTIS). 105 consecutive patients
undergoing HR-SWI as part of their scanning protocol (data
recording period October 2012 May 2013) were assessed. Of
these, nine patients under the care of trust specialty neurology
consultants were previously diagnosed with PD in accordance to
UK Brain Bank Criteria. In another six cases the patients clinical
symptoms raised the possibility of PD, but no formal UK Brain
Bank diagnosis was established, hence patients were labelled as
unclear movement disorder diagnosis and excluded from analysis.
We also excluded patients with structural brainstem pathology
resulting in distortion of the substantia nigra (n = 4). A total of five
scans showed severe artefact due to patient movement preventing
the assessment of the presence of nigrosome-1. This resulted in a
retrospective cohort of 90 cases including 9 clinical PD and 81
patients with clinical diagnoses other than PD without any
documented movement disorder symptoms suggestive of
parkinsonism (Table S1 in File S1). We additionally describe the
sensitivity/specificity analysis when including the 5
non-interpretable scans (n = 95 cases for intent to diagnose analysis).
In the retrospective study, MR imaging was performed on the
same scanner as above, also with a standard eight-channel head
coil, using a standard clinical Phillips Principles of Echo Shifting
with a Train of Observations (PRESTO) sequence. PRESTO is a
HR-T2*/SWI 3D multi-shot fast field echo echo planar imaging
sequence FFE-EPI. TR/TE 16.55/23.29, echo train length 1, Flip
angle 10u, number of slices: 200, voxel size 0.4360.4360.75 mm3,
SENSE factor 2, Scan duration: 2 minutes 36 seconds). The
orientation of acquired axial slices was in alignment with the
splenium and genu of corpus callosum in the sagittal plane.
Nigrosome-1 depiction and swallow tail appearance
MRI scans were visually assessed for absence or presence of
nigrosome-1 hyperintensity independently by two blinded
neuroradiologists with a special interest in neurodegenerative diseases
and more than 20 and 5 years of clinical and research neurological
MRI experience respectively. Scan quality, especially in clinical
scans, can vary and therefore retrospective study MRI scans were
assessed and scored for scan quality (for details on quality
assessment, see supplementary material: MRI scan quality
Nigrosome-1 is located in the posterior third of the substantia
nigra, returns a high signal on SWI in a linear, comma or
wedge shape and is surrounded by low SWI signal intensity
anterior and laterally (pars compacta SN) and medially by low
signal from the medial leminiscus (Fig. 1). Nigrosome-1 and its
surrounding structures have resemblance to the tail of a swallow
on axial imaging HR-SWI (Fig. 1 and Fig. 2).
Presence of the swallow tail/nigrosome-1 was rated for each
hemi-mesencephalon at the level of the caudal posterior SN on
axial and reformatted scans by both raters individually.
Nigrosome-1 scores allowed were present, absent or possibly present.
Given the asymmetrical onset of PD, unilateral absence of
nigrosome-1 was classified as indicative of PD irrespective of the
presence or absence of nigrosome-1 on the other side. Scans were
therefore classified into three groups taking into account
nigrosome-1 assessment. Group I: normal (nigrosome-1 present
bilaterally - or - unilateral nigrosome-1 present and contralateral
possibly present), Group II: non diagnostic (bilateral possibly
present), Group III: abnormal (nigrosome-1 absent unilateral or
bilateral, see also Fig. 3). Reproducibility of nigrosome scoring for
Inter- and Intra-rater (.4 weeks interval between image analysis)
variability was tested by calculation of absolute and kappa
statistics. Consensus agreement for cases which were scored
differently by the two investigators was sought in a final
Figure 3. SWI MRI in PD and Non-PD patients. A. High resolution SWI MRI (3D gradient echo EPI, magnitude image) of a PD patient (left, 60
years, female, UPDRS: 53, HY score 3, nigrosome-1 absent bilaterally) and a control (right, 61 years, female, nigrosome-1 present bilaterally). B. Clinical
high resolution 3D-T2*/SWI MRI (Philips PRESTO sequence), of a PD patient (left, 58 years old, male, nigrosome-1 absent bilaterally) and a non-PD
patient (right, 70 years old, female, diagnosed with an aneurysmal subarachnoid haemorrhage, nigrosome-1 present bilaterally).
Statistical Analysis, Image generation and reporting
Statistical tests were performed using IBM SPSS for windows
(version 19.0) and Microsoft Excel 2010. Demographics were
compared between patients and controls using analysis of
variance. Non-parametric tests were used for group comparisons
in case of non-normal distribution of the data. Values are given as
mean 6 SD unless stated otherwise; significance was defined at
p,0.05. If applicable, sample distribution was assessed by Fishers
exact test. Images for illustration were generated using 3D slicer
(http://www.slicer.org) and GNU Image Manipulation
Program (GIMP V2.8, http://www.gimp.org). QUADAS-2 and
STARD recommendations were used as a guide for analysis and
reporting the study outcomes [22,23].
Inter- and Intra-rater agreement of nigrosome-1
102/109 cases were classified into the same groups by both
raters (109 consisting of 19 prospective study and 90 retrospective
study subjects). Absolute inter-rater agreement was 94%
(kappa = 0.82, p,0.001) and intra-rater agreement 94%
(kappa = 0.82, p,0.001).
Prospective case-control study
PD patients and controls did not differ in age or sex (PD:
68.2611 years, 3 males vs. controls: 66.467.6 years, 6 males).
Disease severity of PD patients ranged from mild to moderate
(UPDRS = 8 to 60, mean 6 SD: 32.5615.4, HY = 1 to 3, mean 6
SD: 1.8560.9, PIGD = 7, TDPD = 3) with a disease duration of
463.4 years (range: 1 to 10 years). No cases were excluded from
the analysis due to poor quality or movement artefact. 16 subjects
(8 PD and 8 controls) were correctly classified by both raters
independently (Fig. 3a). Three subjects (2 PD and 1 control) were
misclassified (1 PD patient after consensus agreement) yielding a
consensus diagnostic accuracy of 84% (sensitivity: 80%, specificity
89%, see also Table S2 in File S1).
Retrospective cross-sectional study
90 consecutive clinical cases (.50 years of age, mean 66.3610.6
years, range 5089.5 years, 49 males) underwent nigrosome-1
review as described above. Both raters considered the quality (QR
- see also supplement methods in File S1) as similar between group
I and III (QR group I: 1.7960.62, QR group III: 1.760.62, n.s.).
Two of 90 patients were classified into group II (Possible presence
of nigrosome-1/uncertain scans). Out of 90 subjects, the same 81
(9 PD and 72 non-PD) were correctly classified by both raters
independently. 86 of 90 patients were correctly classified (all 9 PD
and 77 non-PD) based on consensus rating with similar results for
independent rating (Fig. 3b and 4). Two of the 81 non-PD patients
were wrongly classified as nigrosome-1 absent (group III). Table 1
demonstrates the sensitivity/specificity analysis for both raters
Figure 4. Clinical HR-SWI MRI at 3T (PRESTO sequence) to demonstrate nigrosome-1. Nigrosome-1 assessment of the SN in 4 different
patients (a-d). The first column illustrates the standard axial plane at the level just inferior to red nucleus and the second column the multi-planar
reformat along the axis of the low density signal of the SN (oblique axial). Green arrow tip illustrates nigrosome-1 presence; red arrow tip illustrates
unclear/possible presence of nigrosome-1. a) Non-PD patient (60 years old, female, diagnosed with cognitive impairment and a small cerebral
cavernoma) nigrosome-1 is present bilaterally. b) Non-PD patient (54 year old, female, MRI scan for recurrent loss of consciousness of unknown
cause) nigrosome-1 is present bilaterally but smaller than in (a). c) PD patient (68 years old, male) - Right nigrosome-1 absent, left nigrosome-1
unclear. d) PD patient (65 years old, female) nigrosome-1 absent bilaterally. An example of Group II (bilateral unclear/possible nigrosome-1
presence, n = 2 of 81 non-PD patients) is not demonstrated.
individually and after consensus review of discrepantly scored
cases (consensus diagnostic accuracy: 96%, sensitivity: 100%,
Intent to diagnose analysis of retrospective
crosssectional study cases. To avoid an inflated diagnostic
accuracy resulting from pre-selection based on diagnostic quality,
we also assessed sensitivity/specificity in the cohort of n = 95 (5
non-diagnostic investigations added to the above 90 cases) which
were intended to be assessed for diagnostic purposes. This reduced
the consensus diagnostic accuracy to 91% (sensitivity: 100%,
specificity 90%, Table 2).
N = 90
Analysis of diagnostic accuracy of nigrosome-1 presence to diagnose PD for each rater individually and after consensus assessment of discrepantly rated cases. The
cases were classified according to presence or absence of nigrosome-1 and include nine PD cases and 81 non-PD cases (n = 90).
We demonstrate that standard high resolution susceptibility
weighted MRI at 3T allows the detection of the healthy
nigrosome-1, and its absence in PD, yielding a high diagnostic
accuracy in a clinical population.
The sub-classification of the substantia nigra pars compacta
(SNpc) into nigrosomes and the nigral matrix according to specific
immunohistochemical staining properties was first described by
Damier in 1999 . Calbindin D28K is the antibody used to
demonstrate calbindin, a protein present in striato-nigral afferent
fibres. According to calbindin presence, the SNpc was subdivided
into the nigral matrix (calbindin rich) from the nigrosomes
(calbindin poor). Sixty per cent of all dopamine containing
neurons were found in the nigral matrix and 40% in five different
nigrosomes (nigrosome-1 to nigrosome-5). Even though the
definite functional relevance of this subdivision remains unclear,
Damier found that the largest of the nigrosomes, positioned in the
ventro-lateral substantia nigra (nigrosome-1), was most affected in
PD exhibiting the maximum depletion of dopaminergic cells of
Using high-resolution SWI MRI at 3T, we were able to reliably
visualize the nigrosome in vivo. The appearance of the dorsolateral
SN on standard axial high resolution susceptibility weighted MRI
in healthy controls and in non-PD patients has remarkable
similarity to the tail of a swallow. This is due to the presence of a
high signal intensity wedge previously shown to represent the
nigrosome-1 . Visibility of nigrosome-1 is enhanced by
subtotal outlining of low intensity structures on T2* images
allowing for 3D reconstructions of the wedge-like nigrosome on 7T
- T2* . Direct depiction of SN subcomponents is a new
concept which was very recently introduced using sub-millimetre
ultrahigh-field MRI that allowed detection of the previously
unknown intrinsic contrast mechanisms. Earlier MRI studies in
PD are limited as the boundaries of the substantia nigra pars
compacta and pars reticulata are not well defined on MRI. This is
a recognised source of heterogeneity between studies reporting
quantitative MRI properties of SN pathology .
Intriguingly, the swallow tail sign was absent in patients with
PD, both in the case-control study and the retrospective
crosssectional clinical population study. In the cross-sectional study we
found the diagnostic accuracy ranging between 96% in the
diagnostic scans and 91% in all scans with intent to diagnose.
These findings concord well with the small case-control study at
7T - MRI , proving successful translation of the preliminary
7T finding to a clinically widely used 3T - MRI platform.
Inability to visualise nigrosome-1 on HR-SWI MRI does not
mean nigrosome-1 is completely lost, but that the signal increase
compared to its surround is lost. While we cannot exclude a degree
of nigrosome volume loss, the main effect can be explained by
signal loss of the hyperintense nigrosome-1 (structure 6 in Fig. 1) in
comparison to the adjacent low signal substantia nigra (structure 7
in Fig. 1) and low signal medial leminiscus (structure 5 in Fig. 1)
resulting in homogenous dark appearances. There are two main
possible mechanisms for this, increased iron content or decreased
neuromelanin content with decreased iron storage capacity
leading to more free iron with paramagnetic properties .
Previous MRI studies at 3T or 1.5T assessing iron related PD
induced nigral changes focussed on differences in the whole SN
, attempted subdivision of the SN into pars reticulata and pars
compacta  or used a voxel based morphometric analysis
approach . These studies confirm significant iron related SN
signal alterations on group level, some of which even show
(N = 95, all intended to diagnose)
Analysis of diagnostic accuracy of nigrosome-1 presence to diagnose PD for each rater individually and after consensus assessment of discrepantly rated cases. The
cases were classified according to presence or absence of nigrosome-1 and include the 90 cases from Table 1 and five non-diagnostic scans (n = 95, intended to
correlation to disease severity measures like UPDRS. However,
the highest resolution study  uses voxel sizes of 16162 mm3
which is inappropriate for reliable assessment of small SN
substructures like nigrosome-1. Voxel sizes in the sub-millimetre
region, as used in our 3T MRI study, proved sufficient to reliably
delineate the healthy nigrosome-1.
In our retrospectively studied clinical population, the nigral
swallow tail sign was associated with a negative predictive value of
100% indicating that nigrosome-1 presence was associated with a
very low likelihood of PD. In 2% of the non-PD patients over 50
years of age, the nigrosome was not detectable. This rate is similar
to the rate of prevalence of PD in the elderly  indicating a
possibility of undiagnosed PD in these cases. 5/95 clinical cases
were of poor non-diagnostic quality (caused by patient movement)
prohibiting the assessment for the presence of a swallow tail
appearance. As the scan lasts less than 3 minutes, standard
measures to reduce patient movement during studies, like scan
repetition after patient prompting or additional fixation of the
patients head within the head coil, are likely to increase the rate of
scans of diagnostic quality. Some cases may require light sedation.
The observed rate of non-diagnostic scans without these additional
measures of less than 5.2% compares favourably with a rate of 5
20% failed transcranial ultrasound imaging investigations for PD
In current clinical practice suspected PD can be differentiated
from non-parkinsonian movement disorders like benign tremor
with licensed nuclear medical techniques using e.g. 123ioflupane
(123I, 123I-FP-CIT single photon emission computed tomography
(SPECT) or DaTscan) to demonstrate presynaptic dopamine
transporter loss with up to 95% accuracy . Even though our
control group was chosen not to include patients with uncertain
movement disorders, the comparable high sensitivity/specificity
obtained to diagnose PD vs. non PD based on nigrosomal signal
abnormality highlight the diagnostic potential of 3T SWI scans.
Nuclear medical scans have intrinsic associated high costs, cause
radiation exposure and access to these types of scans is limited in
many countries in contrast to widespread availability of MRI. A
MRI based diagnostic test for PD would have the further
advantage that it can be combined with standard MRI to exclude
focal pathology, assess vascular causes and comorbidity as well as
regional degenerative markers of other atypical parkinsonian
syndromes . Advanced MRI techniques including volumetry
and diffusion tensor imaging (DTI) metrics of midbrain,
cerebellum and pons show promise to aid the differential diagnosis of
atypical parkinsonian syndromes for 1.5T MRI systems with as yet
limited evidence for 3T MRI- DTI systems .
We found that the swallow tail appearances of the healthy
nigrosome can be readily and reliably recognised by trained
radiologists making it an attractive diagnostic imaging sign. This is
clearly advantageous for clinical workflow over previously
proposed MRI markers requiring dedicated postprocessing which
may have contributed to inconsistent results. Nigral diffusion
metrics were reported as promising diagnostic tool for PD but lack
consistency as shown in a recent meta-analysis . Other MRI
based techniques especially iron and neuromelanin sensitive MRI
hold promise to track PD severity , but as yet require
dedicated postprocessing and/or subjective regional
measurements which introduce user dependency. This limits the reliability
and utility of these techniques in standard clinical practice or as
part of research trials. In this study, standard high resolution T2*/
SWI sequences were used for image acquisition in a small
prospective study population but also in a larger standard clinical
population. There was no requirement for complicated post
processing prior to visual assessment for presence or absence of
nigrosome-1 which confirms ease of usability and attractiveness of
this technique for everyday clinical use.
Even though the patients of the prospective arm of this study
were clinically well characterised, only limited clinical information
was available for the retrospective study of patients. Even if the
likelihood of undiagnosed PD patients within the non-PD group of
the retrospective study is low (2% in .60 year olds and majority of
patients receive follow up and treatment for a non-PD related
condition in our institution), we cannot exclude the possibility that
a small number of non-PD classified patients have preclinical PD.
In the context of biases of accuracy studies this could be
considered as a disease spectrum bias and could potentially
falsely raise the sensitivity of the proposed test .
The avoidance of a case-control design and the retrospective
study approach to assess diagnostic accuracy is in accordance to
guidance from QUADAS-2 (Revised Tool for the Quality
Assessment of Diagnostic Accuracy studies ). However, in
the retrospective study arm we had to exclude cases with clinical
movement disorder type symptoms but no definitely established
diagnosis of PD (n = 6 of 105 patients) and our PD patient cohort
only included patients with clinically established PD. Therefore we
are unable to comment on the timing of nigrosome changes in
relation to the onset of parkinsonian symptoms and disease
severity measures. Longitudinal studies of subjects with MR absent
nigrosomes will allow to investigate the predictive value of this
technique in populations at high risk of developing PD.
Independent prospective validation studies are needed to assess
the trajectory of MRI nigrosome-1 changes in relation to the
premotor and motor stages of PD and to correlate nigrosome-1
changes with loss of presynaptic dopamine transporters as
demonstrated by nuclear medical scan techniques such as
The healthy nigrosome-1 can be readily depicted on
highresolution 3T - SWI giving rise to a swallow tail appearance of
the dorsolateral substantia nigra, and this feature is lost in PD.
Visual radiological assessment yielded a high diagnostic accuracy
for PD vs. an unselected clinical control population. Assessing the
substantia nigra on SWI for the typical swallow tail appearance
has potential to become a new and easy applicable 3T MRI
diagnostic tool for nigral degeneration in PD.
File S1 Supporting methods, Tables S1 and S2. Methods:
MRI scan quality assessment. Table S1: Leading diagnosis/
symptoms of patients included in the retrospective review of high
resolution T2* weighted imaging of the SN at 3T. Table S2:
Analysis of diagnostic accuracy of nigrosome-1 presence to
diagnose PD in the prospective study.
We would also like to thank PD research study nurses of the Royal Derby
Hospital for support with participant recruitment and assessment, Sharon
Foreman for continuous administrative help and all study volunteers for
their participation. We would like to thank Dr Chris Tench for providing
the NeuRoi software.
Conceived and designed the experiments: STS PSM NB PAG DPA.
Performed the experiments: STS DPA. Analyzed the data: STS MA DPA.
Contributed reagents/materials/analysis tools: STS DPA. Wrote the
paper: STS MA PSM NB DPA.
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