Journal of Parkinson’s Disease xx (20xx) x–xx 1

DOI 10.3233/JPD-150733
IOS Press

1 Research Report

2 How I do it: Clinical Application

of Brain MRI in the Diagnostic

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4 Work-up of Parkinsonism

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5 Frederick J.A. Meijera,∗ , Bozena Goraja,b , Bastiaan R. Bloemc and Rianne A.J. Esselinkc
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a Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen,
7 The Netherlands
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b Department of Diagnostic Imaging, Medical Center of Postgraduate Education, Warsaw, Poland
c Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical

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10 Center, Nijmegen, The Netherlands

Accepted 8 February 2017

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11 Abstract. Differentiating Parkinson’s disease and atypical parkinsonism on clinical parameters is challenging, especially
12 in early disease courses. This is due to large overlap in symptoms and because the so called red flags, i.e. symptoms
13 indicating atypical parkinsonism, have not (fully) developed. Brain MRI can aid to improve the accuracy and confidence
14 about the diagnosis. The main purpose of brain MRI is to assess cerebrovascular damage, and to exclude other possible – and
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15 sometimes treatable – causes of parkinsonism, such as normal pressure hydrocephalus. Furthermore, brain MRI can support
16 the possible or probable diagnosis of a specific form of atypical parkinsonism. In the current paper, we discuss when brain
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17 MRI should be performed in the diagnostic work-up of parkinsonism, our preferred brain MRI scanning protocol, and the
18 diagnostic value of specific abnormalities.

19 Keywords: Atypical parkinsonism, brain, magnetic resonance imaging, Parkinson’s disease

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20 INTRODUCTION OF THE CLINICAL can aid to improve the accuracy and confidence about 29

21 DILEMMA the diagnosis, which is relevant for treatment deci- 30

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sion making and for prognosis estimation. The main 31

22 Parkinson’s disease (PD) and the different forms purpose of brain MRI is to assess cerebrovascular 32

23 of atypical parkinsonism (AP) are clinical diagnoses. damage, and to exclude other possible – and some- 33

24 Differentiating PD and AP on clinical parameters times treatable – causes of parkinsonism, such as 34

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25 is challenging, especially in early disease courses. normal pressure hydrocephalus. Furthermore, brain 35

26 This is due to (1) large overlap in symptoms and (2) MRI can support the possible or probable diagnosis 36

27 because the so called red flags, i.e. symptoms indicat- of a specific form of AP [3]. More advanced MRI 37

28 ing AP, have not (fully) developed [1, 2]. Brain MRI and functional neuro-imaging techniques, includ- 38

ing functional-MRI and nuclear imaging techniques 39

∗ Correspondence to: Frederick J.A. Meijer, M.D., Ph.D., such as PET and SPECT, have provided a more 40
Department of Radiology and Nuclear Medicine, Radboud
University Medical Center, P.O. 9101, 6500 HB, Nijmegen,
comprehensive understanding of the complex neu- 41

The Netherlands. Tel.: +31 24 3614546; Fax: +31 24 3540866; robiological changes in PD and AP and are expected 42

E-mail: Anton.Meijer@radboudumc.nl. to provide new neuroimaging biomarkers [4]. These 43

ISSN 1877-7171/17/$35.00 © 2017 – IOS Press and the authors. All rights reserved
 2 F.J.A. Meijer et al. / Brain MRI in the Diagnostic Work-up of Parkinsonism

44 techniques are, however, beyond the scope of this sequence. The purpose and limitations of these vari- 74

45 paper. ous sequences are described in Table 1. 75

46 Clinical practice guidelines recommend to perform Conventional brain MRI lacks a specific diagnostic 76

47 a brain MRI once in the course of the disease [5–8]. marker for PD [9]. Cortical atrophy may be related to 77

48 MRI is superior to CT, because of a better resolution the development of dementia in PD, especially when 78

49 and sensitivity to identify structural brain pathology the temporal, occipital and subcortical structures are 79

50 and is therefore the preferred imaging modality [9]. involved [10, 11]. 80

51 A brain CT can be considered in case MRI cannot In patients with specific forms of AP, the cortex, 81

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52 be (safely) performed, for example in case of an basal ganglia, brainstem and cerebellum are the main 82

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53 implanted pacemaker or claustrophobia. cerebral areas of interest as they can be affected by 83

54 In the current paper, we discuss when brain MRI atrophy or signal intensity changes [3, 12, 13]. Exam- 84

55 should be performed in the diagnostic work-up of ples are provided in Figs. 1–4. 85

56 parkinsonism, our preferred brain MRI scanning Atrophy and T2 hyper-intensity changes of the 86

57 protocol, and the diagnostic value of specific abnor- pons (‘hot cross bun’ sign) and middle cerebellar 87

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58 malities. This is of relevance both for neurologists peduncles are suggestive of the cerebellar form of 88

59 and radiologists, as either can signal the presence of multiple system atrophy (MSA). Atrophy and T2 89

60 sometimes subtle abnormalities on brain MRI. hypo-intensity of the putamen may be seen in both 90

the parkinsonian and cerebellar forms of MSA. The 91

putaminal rim sign, seen as a T2 hyper-intense rim

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61 DESCRIPTION OF THE TEST along the outer border of the putamen, is considered 93

to be suggestive of MSA on 1.5T MRI but a nor- 94

62 A routine brain MRI study, at 1.5T or 3T mag- mal finding on 3T MRI [14]. Severe hypo-intensity 95

63 netic field strength, takes about 30 minutes and of the putamen on SWI or T2*, combined with atro- 96
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64 includes different acquisitions, also referred to as phy, is commonly seen in MSA even in early disease 97

65 sequences. We recommend to include T1-weighted stages, and differentiates MSA from other forms of 98

66 and T2 FLAIR, either as 2D or 3D acquisitions. parkinsonism [3, 15]. 99

67 Both transversal and sagittal planes should be Atrophy of the midbrain (‘hummingbird’ sign in 100

68 available. Furthermore, the protocol should include the sagittal plane, or ‘morning glory’ sign in the 101

diffusion-weighted imaging (DWI) and a suscepti- transversal plane), and atrophy with signal inten-
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69 102

70 bility sensitive sequence, either T2* or susceptibility sity changes of the superior cerebellar peduncles are 103

weighted imaging (SWI). For a more detailed eval- typically observed in progressive supranuclear palsy
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71 104

72 uation of the basal ganglia and small areas of tissue (PSP). MRI-based measurements of the midbrain in 105

73 loss, it is advisable to also include a T2-weighted relation to the pons can be applied for the diagnosis of 106

Table 1
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Brain MRI scanning protocol for the evaluation of patients presenting with parkinsonism
Imaging sequence Scanning time (min) Purpose Limitations
T1-weighted† 5 - Evaluation of brain atrophy and tissue loss Sensitivity to tissue signal-intensity changes
- Signal intensity changes basal ganglia is limited
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T2-weighted† 4 Evaluation of atrophy and signal intensity - Overestimation of cortical atrophy

changes, with attention to the basal - Subtle tissue signal intensity abnormalities
ganglia and brain stem can be missed
T2 FLAIR† 3 Evaluation of white matter changes and Limited sensitivity for abnormalities in the
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tissue loss thalamus and brainstem in 2D FLAIR

T2* or SWI 2–5 - Evaluation of abnormal iron depositions in
the basal ganglia and brainstem
- Detection of (micro)bleeding
DWI 2 Evaluation of restricted tissue diffusion,
mainly in acute infarction but also in
neurodegenerative disease such as
Creutzfeldt-Jakob disease.
- Susceptible to artifacts
- Highly dependent on magnetic field
strength
- Brain iron accumulation is age dependent
- Susceptible to artifacts
- Limited spatial resolution

† Either 2D or 3D acquisitions. The scanning protocol should include both axial and sagittal planes.
 F.J.A. Meijer et al. / Brain MRI in the Diagnostic Work-up of Parkinsonism 3

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Fig. 1. Upper row, patient diagnosed with MSA. Atrophy of the putamen can be depicted on the T2-weighted sequence (left image), while
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pronounced susceptibility changes of the putamen is better seen on a SWI sequence (right image). Lower row, T2-weighted and SWI images
of a healthy control subject for comparison.

107 PSP [16, 17]. Hypo-intensity changes of the red and mild general atrophy can be seen in some cases. 121
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108 dentate nuclei on SWI or T2* could possibly provide In case of pronounced ventricular dilatation and 122

109 a new diagnostic marker for PSP, but this observation enlargement of the Sylvian fissure, normal pressure 123

110 remains to be assessed in a larger cohort [15]. hydrocephalus should be included in the differential 124

111 There is a strong correlation between clinically diagnosis (Fig. 5). A decreased angle of the corpus 125
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112 diagnosed corticobasal syndrome and asymmetric callosum in the coronal plane (<80◦ ) can distinguish 126

113 atrophy of the cerebral hemispheres. Although cor- normal pressure hydrocephalus from ex-vacuo ven- 127

114 ticobasal degeneration (CBD) is characterized by ticulomegaly [19]. 128

115 asymmetrical cortical atrophy affecting the parietal The FLAIR sequence is useful for the evalua- 129

116 lobe, the possible underlying pathology of corti- tion of tissue loss and gliosis commonly seen in 130

117 cobasal syndrome also includes PSP, frontotemporal vascular brain damage, which can support the diag- 131

118 dementia or Alzheimer disease [18]. nosis of vascular parkinsonism [20–22]. Vascular 132

119 Dementia with Lewy bodies (DLB) lacks spe- parkinsonism should be considered in case of lacu- 133

120 cific diagnostic markers on brain MRI, although nar infarctions and white matter lesions (signs of 134
4 F.J.A. Meijer et al. / Brain MRI in the Diagnostic Work-up of Parkinsonism

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Fig. 2. Subject diagnosed with the cerebellar form of MSA. Left image, T2-weighted transversal sequence demonstrating pontine atrophy

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with the ‘hot cross bun’ sign (encircled). Middle image, FLAIR hyper-intense signal intensity changes of the middle cerebellar peduncles
(arrows). Right image, T1-weighted sagittal plane demonstrating pontocerebellar atrophy.

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Fig. 3. T1-weighted images in transversal (left image) and sagittal (middle image) planes demonstrating atrophy of the midbrain, also referred
to as the ‘morning glory’ sign and ‘hummingbird’ sign. The subject was diagnosed with PSP. Right image, T1-weighted sagittal plane of a
healthy subject for comparison.
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Fig. 4. Axial T2 FLAIR sequences. Left image, asymmetrical cortical atrophy (encircled) in a patient with corticobasal syndrome. Right
image, hyperintense white matter changes and lacunar infarction (arrows) in a patient diagnosed with vascular parkinsonism.
 F.J.A. Meijer et al. / Brain MRI in the Diagnostic Work-up of Parkinsonism 5

important drawback of quantitative DTI is that pat- 161

terns derived from group-wise comparisons cannot be 162

applied directly to individual patients, as validated 163

diagnostic criteria are generally lacking. The exact 164

role of diffusional changes in the diagnostic process 165

of PD or AP is therefore still under debate. 166

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DISCUSSION 167

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We have provided an overview of clinical brain 168

MRI scanning protocol requirements in the diag- 169

nostic work-up of patients with parkinsonism. 170

Importantly, the diagnosis of PD and specific forms 171

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of AP remain clinical diagnoses according to the 172

current diagnostic criteria/standards. Ancillary inves- 173

tigations can yield specific clues and can be of 174

supportive value for a specific possible or probable 175

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diagnosis. Currently, a definite or even a probable 176

Fig. 5. Coronal FLAIR image in a patient diagnosed with normal

diagnosis cannot be made based on brain MRI alone. 177

pressure hydrocephalus. Pronounced dilatation of the lateral ven- Moreover, sensitivity and specificity of certain spe- 178

tricles and dilation of the Sylvian fissure (encircled). Typically, cific abnormalities on conventional brain MRI for 179
there is no sulcal widening at the vertex (arrow). A decreased the different forms of AP are variable and depend 180
corpus callosum angle (<80◦ ) can distinguish normal pressure
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hydrocephalus from ex-vacuo venticulomegaly.
on disease stage, ranging from reasonably good (e.g. 181

pontocerebellar atrophy in advanced stage MSA-C 182

with reported specificity of 90–100%) to rather poor 183

135 small vessel disease), and is less frequently associ- (e.g. cortical atrophy with reported sensitivity and 184

136 ated with large vessel infarctions [21]. Differentiation specificity for AP of 40–70%) [28]. Clinically as 185

with Parkinson’s disease can be challenging, as con- well as in brain MRI, the diagnostic uncertainty is
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137 186

138 current vascular lesions are relatively common in largest in early disease phases, because abnormali- 187
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139 patients with PD [23]. The evaluation of signal ties may not yet have developed. This is supported by 188

140 intensity changes of the thalamus, brainstem and the few longitudinal imaging studies that performed 189

141 white matter lesions using a 3D FLAIR sequence serial MRI scans in one individual over time [29, 30]. 190

142 is superior to a conventional 2D FLAIR sequence It is therefore appropriate to critically review the 191

143 [24, 25]. common recommendation that brain MRI should be 192
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144 The DWI sequence is sensitive to early ischemic performed as a standard procedure in all patients pre- 193

145 changes after stroke, identification of which can have senting with a form of parkinsonism [5–8]. At our 194

146 immediate consequences for secondary prophylaxis. center, we refrain from brain MRI in patients pre- 195

147 DWI can also be evaluated in a quantitative manner, senting with classical symptoms of idiopathic PD, 196
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148 as changes in diffusivity seem to represent a quanti- i.e. an asymmetric pattern without any red flags and 197

149 tative measure of microstructural integrity of white – preferably – a satisfactory response to a normal 198

150 matter tracts and gray matter structures, and accord- dose of dopaminergic medication. We do perform a 199

151 ingly microstructural damage in neurodegenerative brain MRI in patients with an atypical disease course, 200
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152 disorders such as PD and AP [3]. Diffusion tensor since finding a specific abnormality might suggest 201

153 imaging (DTI) provides additional directional infor- (a specific form of) AP, at the same time realizing 202

154 mation of tissue diffusivity, and hence more detailed that MRI without abnormalities does not exclude any 203

155 measures of microstructural integrity. Previous stud- form of AP. The added value of brain MRI is great- 204

156 ies indicate that DWI and DTI measures of the basal est in patients with a possible underlying treatable 205

157 ganglia, brainstem and cerebellum seem to be able to cause of their parkinsonism, such as patients sus- 206

158 accurately identify subjects diagnosed with PD and pected of having normal pressure hydrocephalus or 207

159 different forms of AP, even when no abnormalities are patients who might have underlying cerebrovascular 208

160 seen on conventional MRI sequences [3, 26, 27]. An pathology. 209
 6 F.J.A. Meijer et al. / Brain MRI in the Diagnostic Work-up of Parkinsonism

210 Finally, it is necessary to briefly mention the impor- techniques rely on algorithms analyzing imaging data 262

211 tance of brain MRI as part of the pre-operative without a-priori hypotheses, based on which clas- 263

212 work-up in PD patients scheduled to undergo a deep sifiers can be constructed for pattern recognition at 264

213 brain surgical procedure. Appropriate patient selec- the individual level [37, 38]. Compared with a single 265

214 tion for this procedure is of critical importance [31]. imaging technique, the advantage of using multiple 266

215 Performing MRI after deep brain stimulation surgery techniques is to extract more features in order to more 267

216 with an implanted electrode is restricted, and feasible accurately profile specific neurodegenerative pathol- 268

217 only under stringent conditions. ogy [38]. 269

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218 How can we increase the diagnostic value of brain Finally, besides optimizing the MRI scanning pro- 270

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219 MRI? A first approach is to further evaluate the merits tocol and applying new neuro-imaging techniques, 271

220 of existing MRI protocols. Performing more longi- the level of experience of the physician reading the 272

221 tudinal imaging studies along with detailed clinical study needs to be taken into account and optimized 273

222 follow-up allows us to determine when in the course accordingly. 274

223 of the disease specific abnormalities are likely to

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224 emerge. Ideally MRI findings should be correlated ACKNOWLEDGMENTS 275

225 with a “silver standard” diagnosis (based on clinical

226 parameters at long term follow-up) and if possible This work was supported by an unrestricted center 276

227 the gold standard diagnosis (based on post-mortem grant of the National Parkinson Foundation (NPF). 277

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228 brain examination). We used this former approach We thank Yvonne Hoogeveen and Dr. Stefan Steens 278

229 in a follow-up study of 156 patients presenting with for proofreading of the manuscript. 279

230 parkinsonism, and showed that a comprehensive set

231 of clinical tests provides good accuracy to differenti- CONFLICT OF INTEREST 280
232 ate PD from AP, and that the added diagnostic value
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233 of brain MRI is relatively highest for those patients The authors have no conflict of interest to report. 281
234 where the baseline clinical diagnostic certainty is
235 lowest [28, 32]. REFERENCES 282
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