A new MR imaging index for differentiation of progressive supranuclear palsy-parkinsonism from Parkinson's disease

Accepted Manuscript A new MR imaging index for differentiation of progressive supranuclear palsyparkinsonism from Parkinson's disease Aldo Quattrone, Maurizio Morelli, Salvatore Nigro, Andrea Quattrone, Basilio Vescio, Gennarina Arabia, Giuseppe Nicoletti, Rita Nisticò, Maria Salsone, Fabiana Novellino, Gaetano Barbagallo, Emilio Le Piane, Pierfrancesco Pugliese, Domenico Bosco, Maria Grazia Vaccaro, Carmelina Chiriaco, Umberto Sabatini, Virginia Vescio, Carlo Stanà, Federico Rocca, Domenico Gullà, Manuela Caracciolo PII:

S1353-8020(18)30327-4

DOI:

10.1016/j.parkreldis.2018.07.016

Reference:

PRD 3737

To appear in:

Parkinsonism and Related Disorders

Received Date: 19 April 2018 Revised Date:

19 July 2018

Accepted Date: 24 July 2018

Please cite this article as: Quattrone A, Morelli M, Nigro S, Quattrone A, Vescio B, Arabia G, Nicoletti G, Nisticò R, Salsone M, Novellino F, Barbagallo G, Le Piane E, Pugliese P, Bosco D, Vaccaro MG, Chiriaco C, Sabatini U, Vescio V, Stanà C, Rocca F, Gullà D, Caracciolo M, A new MR imaging index for differentiation of progressive supranuclear palsy-parkinsonism from Parkinson's disease, Parkinsonism and Related Disorders (2018), doi: 10.1016/j.parkreldis.2018.07.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Quattrone et al. 1 A new MR imaging index for differentiation of progressive supranuclear palsy-parkinsonism from Parkinson’s disease

Aldo Quattrone a, b, *, Maurizio Morelli b, c, Salvatore Nigro b, Andrea Quattrone c, Basilio Vescio d,

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Gennarina Arabia b, c, Giuseppe Nicoletti b, Rita Nisticò b, Maria Salsone b, Fabiana Novellino b, Gaetano Barbagallo c, Emilio Le Piane e, Pierfrancesco Pugliese f, Domenico Bosco g, Maria Grazia

Rocca b, Domenico Gullà b, Manuela Caracciolo b.

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Vaccaro b, Carmelina Chiriaco b, Umberto Sabatini h, Virginia Vescio h, Carlo Stanà h, Federico

Neuroscience Centre, Magna Graecia University, Catanzaro, Italy.

b

Neuroimaging Research Unit, Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy.

c

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a

Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University,

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Catanzaro, Italy.

Biotecnomed, S.C.aR.L, Catanzaro, Italy.

e

Department of Neurology, Pugliese-Ciaccio Hospital, Catanzaro, Italy.

f

Neurology Unit, Annunziata Hospital, Cosenza, Italy.

g

San Giovanni di Dio Hospital, Crotone, Italy.

h

Institute of Neuroradiology, Magna Graecia University, Catanzaro, Italy.

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*

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d

Corresponding author: Prof. Aldo Quattrone

Address: Neuroscience Centre, Magna Graecia University, and Neuroimaging Research Unit, Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy. Telephone number: +39-0961-3695918; Fax number: +39-0961-3647177; E-mail address: [email protected]

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Title characters (space included): 114

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Word abstract count: 249 Words text count: 3023 Number of Tables: 3

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Number of Figures: 1 Number of Supplementary Tables: 4

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Number of Supplementary Methods: 1 Number of References: 30

Keywords:

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Progressive supranuclear palsy-parkinsonism Magnetic Resonance Parkinsonism Index

Magnetic Resonance Parkinsonism Index 2.0

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Third ventricle

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Pons area-midbrain area ratio

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ABSTRACT Introduction: Differentiating clinically progressive supranuclear palsy-parkinsonism (PSP-P) from

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Parkinson’s disease (PD) may be challenging, especially in the absence of vertical supranuclear gaze palsy (VSGP). The Magnetic Resonance Parkinsonism Index (MRPI) has been reported to accurately distinguish between PSP and PD, yet few data exist on the usefulness of this biomarker for the

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differentiation of PSP-P from PD.

Methods: Thirty-four patients with PSP-P, 46 with PSP-RS, 53 with PD, and 53 controls were

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enrolled. New consensus criteria for the clinical diagnosis of PSP were used as the reference standard. The MRPI, and a new index termed MRPI 2.0 including the measurement of the third ventricle width (MRPI multiplied by third ventricle width/frontal horns width ratio), were calculated on T1-weighted MR images.

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Results: The MRPI differentiated patients with PSP-P from those with PD with sensitivity and specificity of 73.5% and 98.1%, respectively, while the MRPI 2.0 showed higher sensitivity (100%) and similar specificity (94.3%) in differentiating between these two groups. Both biomarkers showed

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excellent performance in differentiating PSP-P patients with VSGP from those with PD, but the MRPI 2.0 was much more accurate (95.8%) than MRPI in differentiating PSP-P patients with

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slowness of vertical saccades from PD patients. Conclusion: The MRPI 2.0 accurately differentiated PSP-P patients from those with PD. This new index was more powerful than MRPI in differentiating PSP patients in the early stage of the disease with slowness of vertical saccades from patients with PD, thus helping clinicians to consolidate the diagnosis based on clinical features, in vivo.

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1. Introduction According to the Movement Disorder Society criteria for clinical diagnosis of progressive

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supranuclear palsy (PSP) [1], probable PSP-P is characterized by ocular motor dysfunction (vertical supranuclear gaze palsy, VSGP, or slow velocity of vertical saccades) associated with a levodoparesponsive or levodopa-resistant parkinsonism.

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Differentiating PSP-P from Parkinson’s disease (PD) may be challenging, especially in the early stages of the disease when the clinical signs are often subtle [2-5]. VSGP is the most specific sign of

the diagnosis difficult [2, 5].

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PSP-P [3] but it may occur later or never in these patients during the course of the disease, making

Quantitative MRI measurements have been proven to be useful markers to differentiate patients with PSP from those with PD. The Magnetic Resonance Parkinsonism Index (MRPI: pons area-midbrain

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area ratio multiplied by middle cerebellar peduncles width-superior cerebellar peduncles width ratio) has been proven to accurately differentiate PSP from PD patients on an individual basis [6-15]. A recent report from the Movement Disorder Society-endorsed PSP Study Group [12] indicated that the

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MRPI and the midbrain area-pons area ratio are the most reliable biomarkers for the diagnosis of PSP-RS, supporting clinical diagnoses in both the early and late stages of the disease. The MRPI has

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also been demonstrated to be more powerful than clinical features in predicting the appearance of VSGP in PSP-P patients [16]. At present, however, few studies have investigated the usefulness of the MRPI for differentiating between patients with PSP-P from those with PD [8, 16]. In the current study, we used a large sample of patients with PSP-P, PSP-RS, and PD to assess the specificity and sensitivity of the MRPI and of a newer version, the MRPI 2.0, for differentiating PSP-P from other groups, using established new clinical criteria for diagnosing PSP as the reference standard [1]. This new imaging biomarker (MRPI 2.0) is based on the combined evaluation of the

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MRPI and the third ventricle (3rdV) width, a cerebral structure that has been reported to be enlarged in PSP patients [17]. The pons area to midbrain area ratio (P/M), a biomarker which has been

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reported to accurately differentiate PSP from PD was also calculated [6, 18-19]

2. Materials and methods

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2.1 Study subjects

Thirty-six patients with PSP-P, 49 patients with PSP-RS, 56 patients with idiopathic PD, and 57

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sex- and age-matched healthy control subjects were recruited consecutively from those referred to the Institute of Neurology at the University of Catanzaro, Italy between 2009 and 2017. Clinical diagnoses for all patients were established by one trained physician (M.M.) with more than 10 years of experience in movement disorders using international diagnostic criteria [1, 20-21]. Patients

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enrolled before 2017 were reclassified according to the recent diagnostic criteria for PSP-RS and PSP-P [1]. A subset of patients included in the current study has been reported previously [14, 16]. For each patient, a complete medical history with neurological examination were performed,

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including the Unified Parkinson’s Disease Rating Scale - Motor Examination (UPDRS-ME) when patients were in the off-state (off medications overnight) [22], the Hoehn and Yahr (H-Y) rating scale

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[23], and the Mini Mental State Examination (MMSE) [24]. Levodopa response was assessed both in the off-state (off medications overnight) and two hours after drug administration as a clinical improvement of 20% or greater on the UPDRS-ME score. In each participant, reduced velocity (and amplitude) of voluntary upward and downward saccades was considered as the criterion for slowness of vertical saccades. A clear limitation of the range of voluntary gaze in the vertical plane more than in the horizontal plane, affecting both up- and downgaze, more than expected for age was considered as the highest level of certainty for vertical ocular motor dysfunction [1].

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Because the modality of clinical assessment of ocular motor dysfunction was not substantially different between previous [20] and new criteria [1] for diagnosis of PSP, the vertical ocular motor

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dysfunction assessed with Litvan’s criteria [20] was here stratified by two levels of certainty according the new PSP diagnostic criteria [1]: O1 (highest level, VSGP) and O2 (mid-level, slowness of vertical saccades). The O1 and O2 levels must be associated with postural instability (P1, repeated

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unprovoked falls within 3 years; or P2, tendency to fall on the pull test within 3 years) for a diagnosis of PSP-RS, while these ocular signs must be associated with A2 (parkinsonism levodopa resistant) or

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A3 (parkinsonism levodopa responsive) for a diagnosis of PSP-P. The exclusion criteria for patients were: history of neuroleptic use within the past six months, evidence of vascular lesions such as lacunar infarctions in the basal ganglia and/or subcortical vascular lesions with diffuse periventricular signal alterations or normal pressure hydrocephalus (NPH), suggested by abnormal

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radiologic signs such as reduced callosal angle (CA) and enhanced Evans index (EI) [25], evidence of normal striatal uptake of dopamine transporter on 123I-FP-CIT-SPECT. We excluded patients with vascular lesions or NPH because these diseases can influence MRPI 2.0 values by causing

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enlargement of cerebral ventricules or atrophy of midbrain [25-26]. None of the healthy controls had a history of neurologic, psychiatric, or other major medical illnesses. All study participants gave

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written informed consent, and the study was approved by the Local Institutional Ethical Committee, according to the Helsinki Declaration.

2.2 MR Imaging protocol

After clinical evaluation, brain MRI was performed in all patients and control subjects using a 3T MR750 GE MRI scanner with an 8-channel head coil. The MRI protocol included: 3-dimensional T1-weighted volumetric spoiled gradient echo (GE), T2-weighted fast spin echo, and T2-weighted

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fluid attenuated inversion recovery sequences. Further information is given in Supplementary

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Methods.

2.3 Morphometric measurements

Using MRI T1-weighted volumetric images, an off-line resectioning procedure was used to expose

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high-spatial-resolution views of the 3rdV and the frontal horns (FH) of the lateral ventricles. In particular, a volumetric slab (1 mm section thickness) parallel to the plane that intersected the

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anterior and posterior commissures was placed on a midsagittal view. The 3rdV width was measured on an axial slice generated at the level of both the anterior and posterior commissures by averaging three different measurements of the maximum linear distance between the lateral borders (Fig.1). The FH were evaluated on the axial view showing their maximal dilatation, and the largest left-to-

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right width was measured. The 3rdV width was divided by the maximal width of FH thus correcting for different FH size in each subject. CA and EI were measured according to a procedure previously described [25]. Two independent raters with more than 10 years of experience in neuroradiology and

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blinded to patients’ data manually measured the 3rdV width and the maximal FH width. Automated measurement of the pons-to-midbrain area ratio (P/M) and MRPI was performed using

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the method described previously (http://mrpi.unicz.it) [6, 13-15]. MRPI 2.0 values were obtained by multiplying the MRPI value by the 3rdV width-FH width ratio (3rdV/FH) (MRPI 2.0=MRPI

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3rdV/FH). We also calculated a new P/M index (P/M 2.0) multiplying P/M value by 3rdV/FH (P/M 2.0=P/M . 3rdV/FH).

To assess the intra-rater reliability, one of the two raters performed a second evaluation 1 week after the first. Finally, to verify the agreement in manual measurements between the two raters, the interrater reliability was calculated.

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2.4 Statistical analysis Differences between sexes and dopaminergic responsiveness distributions were assessed by Fisher's

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exact test. Continuous variables were compared using ANOVA followed by pairwise t-tests or the Kruskal-Wallis test followed by pairwise Wilcoxon rank sum tests. We assessed sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic

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accuracy of the 3rdV, 3rdV/FH, P/M, P/M 2.0, MRPI, and MRPI 2.0 in differentiating PSP from PD and controls. To assess intra-rater and inter-rater reliability, intraclass correlation coefficients were

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calculated. Statistical analyses were performed using R statistical software (R for Unix/Linux, version 3.1.1, the R Foundation for Statistical Computing, 2014). More details are given in the

3. Results

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Supplementary methods.

The demographic, clinical, and neuroimaging data of patients and control subjects are summarized in

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Table 1. We excluded 12 individuals (2 patients with PSP-P, 3 with PSP-RS, 3 with PD, and 4 control subjects) from the analysis because MRI examination showed vascular lesions (1 PSP-RS, 2 PD; 4

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controls) or radiologic signs suggestive of NPH (2 PSP-P and 2 PSP-RS, 1 PD). Patients with PSPRS showed greater disease severity, higher cognitive impairment, and worse levodopa responsiveness than patients with PD, whereas patients with PSP-P showed intermediate values for these clinical variables between PSP-RS and PD patients (Table 1). Figure 1 shows an example of the manual measurements of the 3rdV width and the FH width on the axial T1-weighted images, in a control patient, in a patient with PD and in a PSP-P patient. The 3rdV width and the 3rdV/FH, P/M, P/M 2.0 MRPI, and MRPI 2.0 values were significantly larger in both the PSP-RS and PSP-P groups

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than in the PD patients and controls (Table 1 and supplementary Table 1). P/M, MRPI and MRPI 2.0 values were significantly larger in PSP-RS than PSP-P patients while there were no significant

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differences regarding the 3rdV width, 3rd V/FH, and P/M 2.0 between the two PSP groups. (Table 1 and supplementary Table 1). The sensitivity, specificity, PPV, NPV, and diagnostic accuracy of all investigated biomarkers in differentiating patients with PSP from those with PD and control subjects

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are shown in Table 2 and supplementary Table 2. MRPI and MRPI 2.0 differentiated patients with PSP-RS from those with PD and controls with a very high diagnostic accuracy (100%) (Table 2). The

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MRPI differentiated patients with PSP-P from those with PD with a sensitivity and specificity of 73.5% and 98.1% respectively, whereas the MRPI 2.0 showed higher sensitivity (100%) and similar specificity (94.3%) (Table 2). The 3rdV width and 3rdV/FH, P/M and P/M 2.0 showed a worse performance than MRPI 2.0 (supplementary Table 2). Similar performance of P/M 2.0 and MRPI 2.0

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in differentiating PSP from PD and controls was obtained when patients with NPH or cerebral vascular lesions were included in the analysis (supplementary Table 3). The demographic, clinical, and radiological data of patients with PSP-P, stratified by two levels of certainty for vertical ocular

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motor dysfunction (level O1 with VSGP, PSP-P/O1; level O2 with slowness of vertical saccades, PSP-P/O2), are listed in supplementary Table 4. PSP-P/O1 patients showed greater disease severity,

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higher cognitive impairment, worse levodopa responsiveness, and increased mean values for all MRI morphometric measurements than PSP-P/O2 patients (supplementary Table 4). The sensitivity, specificity, PPV, NPV, and diagnostic accuracy of the MRPI and MRPI 2.0 in differentiating patients with PSP-P (O1 or O2 levels) from patients with PD are shown in Table 3. Both the MRPI and MRPI 2.0 showed excellent performance in differentiating PSP-P/O1 patients from those with PD but only the MRPI 2.0 differentiated PSP-P/O2 patients from those with PD with very high diagnostic accuracy (95.8%) (Table 3). The 3rdV width, the 3rdV/FH, P/M, and P/M 2.0 showed a worse

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performance than MRPI 2.0 when PSP-P/O1 or PSP-P/O2 were compared with PD (supplementary Table 5). There was excellent intra-rater (intra-class correlation coefficients: 3rdV width, 0.993; FH

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width, 0.991; 3rdV/FH, 0.995) and inter-rater (intra-class correlation coefficients: 3rdV width, 0.982; FH width, 0.987; 3rdV/FH, 0.989) agreement.

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4. Discussion

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Our study demonstrates that the MRPI 2.0 was more accurate than MRPI in differentiating patients with PSP-P and those with PSP-P/O2 from patients with PD. The better performance of MRPI 2.0 can be attributed to the measurement of the third ventricle width, a brain structure usually enlarged in PSP, which was included in the calculation of this new index.

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Differentiating PSP-P from PD is challenging because the PSP-P phenotype shows a clinical picture similar to that observed in PD patients, and a more favorable disease course compared with PSP-RS [2-5]. In a retrospective review, no clinical feature distinguished PSP-P from PD in the early stage of

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the disease [3]. VSGP is the most specific sign of the disease compared with PD, but it often occurs late in the course of the disease [3, 5]. A recent retrospective study in 19 patients demonstrated that

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VSGP appeared between 7 and 19 years after the disease onset [5]. In the absence of VSGP, slowness of vertical saccades is the most specific neurologic sign for differentiating PSP-P from PD. This sign, however, is often difficult to evaluate, and it is possible that some patients with PD may be misdiagnosed with PSP-P and vice versa. The MRPI has been widely proposed as a useful biomarker to support clinicians in diagnosing PSP [6-15]. Moreover, MRPI has proven to be useful for predicting the clinical evolution towards PSP phenotypes of patients affected by undetermined parkinsonism [27-28] or the appearance of VSGP in

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patients with PSP-P [16]. To date, few studies have investigated the use of MR morphometric measures for the differentiation of PSP-P from PD. Some authors [8] in a retrospective study on a

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small sample of PSP-P patients found that MRPI differentiated these patients from those with PD with low diagnostic sensitivity (70%) and specificity (68%) and others reported 74% accuracy using the volume and fractional anisotropy of the superior cerebellar peduncles [29]. In a previous report,

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we demonstrated that about 50% of patients with a clinical diagnosis of PSP-P had MRPI values that were indistinguishable from those in patients with PD [16]. Very recently some authors using MRI

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diffusion tensor imaging found that microstructural integrity within the dentatorubrothalamic tract in combination with assessment of gait and postural stability differentiated PSP-P from PSP-RS and PD in early to moderately advanced stage [30].

In the current study, the sensitivity and specificity of the MRPI in differentiating PSP-P from PD

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patients were 73.5% and 98.1%, respectively. Our results confirm the low sensitivity of the MRPI already described in a previous study [8], suggesting a limited utility of this biomarker to identify PSP-P patients. Similar results were obtained using the 3rdV width, and 3rdV/FH measurements. By

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contrast, the MRPI 2.0 showed very high sensitivity and specificity in differentiating patients with PSP-P from those with PD. This result can be attributed to a combined evaluation of MRPI with the

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3rdV/FH, a measure which was significantly increased in PSP-P in comparison with PD. Indeed, the combined assessment of structures specifically involved in PSP, such as the midbrain, superior cerebellar peduncles, and 3rdV improved the performance of the MRPI 2.0 in comparison with the MRPI, allowing more accurate differentiation of patients with PSP-P from those with PD. P/M and P/M 2.0 also showed a good performance in differentiating PSP-P from PD but their accuracies were lower than that observed with MRPI 2.0

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According to the new clinical criteria for diagnosing PSP [1], in the current study 15 out of 34 PSP-P patients were in O1 group (VSGP) and 19 PSP-P patients were in O2 group (slowness of vertical

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saccades). All morphometric measures (3rdV width, 3rdV/FH, P/M, P/M 2.0, MRPI, and MRPI 2.0) showed larger values in O1 than in O2 PSP-P patients, thus suggesting a relationship between these measurements and ocular movement dysfunction. In the current study, we found the enlargement of

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the 3rdV width in both O1 and O2 groups in comparison with PD, confirming the involvement of this brain structure also in patients with milder PSP phenotypes [17].

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Both MRPI and MRPI 2.0 accurately differentiated PSP-P/O1 patients from PD patients, while only the MRPI 2.0 was able to distinguish between the PSP-P/O2 and PD patients with very high accuracy. The better performance in PSP-P/O2 patients of MRPI 2.0 compared to MRPI was confirmed using the positive predictive value (PPV). Indeed, in these patients MRPI showed a PPV

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of 63.6%, while MRPI 2.0 had a PPV of 86.4%. These values indicate that a patient suspected of having PSP-P/O2 with a positive result on MRPI 2.0 (value ≥ 2.18) had a higher probability of being a true positive rather than using MRPI, and suggest a limited diagnostic utility of the MRPI to

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identify PSP-P patients in early stage of the disease with slowness of vertical saccades. A possible explanation of this finding can be the lower MRPI values observed in O2 patients than in O1 group.

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Indeed, in PSP-P/O2 patients, MRPI values showed a large overlap with values from patients with PD, suggesting the usefulness of measuring the 3rdV/FH ratio together with midbrain and superior cerebellar peduncles, in patients with a lower degree of ocular dysfunction. P/M and P/M 2.0 showed lower performances than MRPI 2.0 when PSP-P/O1 or PSP-P/O2 were compared with PD. Overall, this result with MRPI 2.0 may have important implications for clinical diagnosis of PSP-P in vivo, because vertical ocular slowness is a clinical sign difficult to evaluate, often leading to misdiagnosis between PD and PSP-P.

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There is now an automated version of the MRPI [13-15] and, although the MRPI 2.0 needs some manual measurements, these new measures are easy to calculate also for people without expertise in

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neuroradiology. Indeed, measurement of the 3rdV width and the 3rdV/FH required only a few minutes, making it easy to incorporate the MRPI 2.0 into routine clinical practice.

There are some limitations to this study. Firstly, we used clinical criteria for disease diagnosis, and

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none of our patients underwent autopsy. Thus, it is possible that some patients, especially those with PSP-P, may have had an incorrect clinical diagnosis. However, clinical evaluations were performed

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according to the new clinical criteria for diagnosing PSP, and were carried out by one of the authors with more than 10 years of experience in movement disorders. Secondly, abnormalities of vertical saccades may occasionally be present both in aging and vascular parkinsonism. However, no patient included in the study had vascular lesions, and patients were matched for age in all groups. Thirdly,

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the 3rdV width and 3rdV/FH values included in the calculation of MRPI 2.0 were independently assessed by two authors who were blinded to patients’ diagnoses, and inter-, and intra-rater evaluations confirmed the high reliability of the measurements. Fourthly, further studies in

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independent and larger patient cohorts are needed to confirm our results. In conclusion, our study demonstrates that MRPI 2.0 accurately differentiated PSP-P patients from

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those with PD. MRPI 2.0 was more powerful than MRPI for the differentiation of PSP-P patients with slowness of vertical saccades from those with PD. Thus, the MRPI 2.0 may help clinicians to confirm the diagnosis of PSP-P, even in the absence of VSGP, in vivo.

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Funding: no funding source is associated with the manuscript.

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Declaration of interest: none.

Author’s contribution

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Aldo Quattrone: conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article, revising it critically for important intellectual content and final approval of the version to be submitted

Maurizio Morelli: acquisition of data, analysis and interpretation of data, revising the article

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critically for important intellectual content and final approval of the version to be submitted Salvatore Nigro: acquisition of data, analysis and interpretation of data, revising the article critically

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for important intellectual content and final approval of the version to be submitted Andrea Quattrone: acquisition of data, analysis and interpretation of data, revising the article

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critically for important intellectual content and final approval of the version to be submitted Basilio Vescio: analysis and interpretation of data, revising the article critically for important intellectual content and final approval of the version to be submitted Gennarina Arabia: acquisition of data, analysis and interpretation of data, revising the article critically for important intellectual content and final approval of the version to be submitted

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Giuseppe Nicoletti: acquisition of data, analysis and interpretation of data, revising the article critically for important intellectual content and final approval of the version to be submitted

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Rita Nisticò: acquisition of data, analysis and interpretation of data, revising the article critically for important intellectual content and final approval of the version to be submitted

Maria Salsone: acquisition of data, analysis and interpretation of data, revising the article critically

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for important intellectual content and final approval of the version to be submitted

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Fabiana Novellino: acquisition of data, analysis and interpretation of data, revising the article critically for important intellectual content and final approval of the version to be submitted Gaetano Barbagallo: acquisition of data, analysis and interpretation of data, revising the article critically for important intellectual content and final approval of the version to be submitted

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Emilio Le Piane: acquisition of data, revising the article critically for important intellectual content and final approval of the version to be submitted

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Pierfrancesco Pugliese: acquisition of data, revising the article critically for important intellectual

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content and final approval of the version to be submitted Domenico Bosco: acquisition of data, revising the article critically for important intellectual content and final approval of the version to be submitted Maria Grazia Vaccaro: acquisition of data, revising the article critically for important intellectual content and final approval of the version to be submitted Carmelina Chiriaco: acquisition of data, revising the article critically for important intellectual content and final approval of the version to be submitted

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Umberto Sabatini: acquisition of data, analysis and interpretation of data, revising the article critically for important intellectual content and final approval of the version to be submitted

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Virginia Vescio: acquisition of data, analysis and interpretation of data, revising the article critically for important intellectual content and final approval of the version to be submitted

Carlo Stanà: acquisition of data, analysis and interpretation of data, revising the article critically for

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important intellectual content and final approval of the version to be submitted

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Federico Rocca: acquisition of data, revising the article critically for important intellectual content and final approval of the version to be submitted

Domenico Gullà: acquisition of data, revising the article critically for important intellectual content and final approval of the version to be submitted

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Manuela Caracciolo: acquisition of data, revising the article critically for important intellectual

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content and final approval of the version

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27. M. Morelli, G. Arabia, F. Novellino, et al., MRI measurements predict PSP in unclassifiable parkinsonisms: a cohort study, Neurology 77 (2011) 1042-1047.

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30. M. Seki, K. Seppi, C. Mueller, Diagnostic potential of dentatorubrothalamic tract analysis in

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progressive supranuclear palsy, Park. Rel. Disord. 49 (2018) 81-87.

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Figure legend:

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Figure 1. Axial T1-weighted volumetric MR images show the third ventricle at the level of the anterior and posterior commissures. Measurements were performed at the level of the anterior (1), middle (2), and posterior (3) sections of the third ventricle. At the bottom, figure shows frontal horns

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of the lateral ventricles on axial view showing their maximal dilatation, in which their largest left-toright width was measured (4), in a control participant (A), a patient with Parkinson’s disease (B) and

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a patient with PSP-P (C). Images show marked dilatation of third ventricle in the PSP-P patient in

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comparison with the Parkinson’s disease patient and the control participant.

ACCEPTED MANUSCRIPT Table 1. Demographic, clinical and neuroimaging data of patients with PSP-parkinsonism, PSPRichardson syndrome, Parkinson’s disease, and control subjects.

PSP-RS (n = 46)

PD (n = 53)

Control subjects (n = 53)

p value

27/7

25/21

39/14

36/17

0.087a

Age at examination, ysb

72.0 ± 5.7 (57-84)

70.4 ± 5.2 (56-84)

70.3 ± 5.2 (61-80)

71.5 ± 5.2 (63-83)

0.36c

Age at disease onset, ysb

64.6 ± 5.6 (52-73)

66.4 ± 5.3 (51-80)

63.4 ± 5.0 (50-74)

\

0.02c

7.3 ± 3.7 (1-14)

3.9 ± 1.7 (1-8)

6.8 ± 3.3 (1-17)

\

< 0.001d

MMSE scoree

23 (11-27)

21 (13-28)

24 (17-28)

27 (25-30)

< 0.001d

UPDRS-ME scoree

37 (21-48)

41 (21-56)

28 (15-52)

\

< 0.001d

H-Y scoree

3 (1.5-4)

4 (2.5-5)

2 (1.5-4)

\

< 0.001d

Levodopa responsivenessf

19 (55.9)

2 (4.3)

53 (100)

\

< 0.001a

Brain MRI measurementsb

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Disease duration, ysb

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Sex (M/F)

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PSP-P (n = 34)

Data

9.3 ± 2.1 (5.6-14.6)

9.3 ± 1.8 (5.6-14.0)

5.8 ± 1.4 (3.2-8.9)

5.8 ± 1.7 (2.1-9.9)

< 0.001c

FH width, mm

37.1 ± 5.7 (20.4-52.5)

36.9 ± 5.3 (21.9-49.1)

35.1 ± 3.7 (26.8-43.1)

34.7 ± 4.6 (25.4-46.7)

0.03c

3rdV-FH ratio

0.25 ± 0.05 (0.18-0.36)

0.25 ± 0.04 (0.17-0.36)

0.16 ± 0.03 (0.09-0.25) 0.17 ± 0.04 (0.06-0.27)

< 0.001c

P/M

5.58 ± 1.2 (3.65-8.76)

6.44 ± 1.2 (4.38-9.20)

4.05 ± 0.5 (2.92-5.12)

3.83 ± 0.4 (2.99-4.75)

< 0.001c

P/M 2.0

1.41 ± 0.4 (0.88-2.60)

1.65 ± 0.5 (0.83-2.87)

0.67 ± 0.2 (0.28-1.00)

0.65 ± 0.2 (0.23-1.18)

< 0.001d

MRPI

14.45 ± 4.5 (8.41-34.49) 20.41 ± 4.7 (13.88-34.92) 9.58 ± 1.6 (6.37-12.47) 9.05 ± 1.3 (6.60-12.12)

< 0.001d

MRPI 2.0

3.68 ± 1.6 (2.18-10.23)

< 0.001d

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3rdV width, mm

1.58 ± 0.4 (0.60-2.38)

1.51 ± 0.4 (0.59-2.28)

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5.23 ± 1.7 (2.50-9.65)

Abbreviations: PSP-P = progressive supranuclear palsy-parkinsonism; PSP-RS = progressive supranuclear palsy-Richardson’s syndrome; PD = Parkinson’s disease; MMSE = mini-mental state examination; UPDRS-ME = unified Parkinson’s disease rating scale-motor examination; H-Y = Hoehn-Yahr; 3rdV = third ventricle; FH = frontal horns of lateral ventricles; P/M = pons to midbrain areas ratio; MRPI = magnetic resonance parkinsonism index. PSP-RS patients included 22 classified as P1-O1 and 24 as P1-O2; PSP-P patients included 8 classified as O1-A2, 7 as O1-A3, 7 as O2-A2, and 12 as O2-A3, according to G. Höglinger et al., 2017 [1]. a

Fisher’s exact test. bData are expressed as mean ± standard deviation (range). cANOVA followed by pairwise t-test with Bonferroni

correction. dKruskal-Wallis test followed by pairwise Wilcoxon rank sum test with Bonferroni correction. eData are expressed as median value (range). fNumber (percentage) of patients who showed a clinical improvement of at least 20% in comparison with that detected in the off state.

ACCEPTED MANUSCRIPT Table 2. MRPI and MRPI 2.0 for differentiation of patients with progressive supranuclear palsy from patients with Parkinson’s disease and control subjects.

Cutoff and statistical values

MRPI

MRPI 2.0

Sensitivity (%)

73.5

Specificity (%)

98.1

PPV (%)

96.2

NPV (%)

85.2

Accuracy (%)

88.5

PSP-P patients vs. control subjects ≥ 11.34a

Cutoff value

85.3

Specificity (%)

98.1

PPV (%) Accuracy (%) PSP-RS patients vs. PD patients Cutoff value Sensitivity (%)

Accuracy (%)

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Specificity (%) NPV (%)

94.3 91.9 100

96.6

96.7

NPV (%)

PPV (%)

100

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Sensitivity (%)

≥ 2.18a

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≥ 12.38a

Cutoff value

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PSP-P patients vs. PD patients

≥ 2.18a 100

98.1 97.1

91.2

100

93.1

98.9

≥ 13.88a

≥ 2.50a

100

100

100

100

100

100

100

100

100

100

≥ 13.88a

≥ 2.50a

100

100

100

100

100

100

100

100

100

100

Cutoff value Sensitivity (%) Specificity (%) PPV (%) NPV (%)

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Accuracy (%)

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PSP-RS patients vs. control subjects

Abbreviations: PSP-P = progressive supranuclear palsy-parkinsonism; PD = Parkinson’s disease; PSP-RS = progressive supranuclear palsy-Richardson’s syndrome; MRPI = magnetic resonance parkinsonism index; PPV = positive predictive value; NPV = negative predictive value. a

Optimal cutoff values were determined by using receiver operating characteristic curve analysis.

ACCEPTED MANUSCRIPT Table 3. MRPI and MRPI 2.0 for the differentiation of patients with progressive supranuclear palsy-parkinsonism with two different levels of certainty for vertical ocular motor dysfunction (O1

Cutoff and statistical values

MRPI 2.0

≥ 12.38a

≥ 2.91a

Sensitivity (%)

100

100

Specificity (%)

98.1

100

PPV (%)

93.8

100

NPV (%)

100

100

98.5

100

≥ 11.34a

≥ 2.18a

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MRPI

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and O2) from patients with Parkinson’s disease.

PSP-P patients with O1 level vs. PD patients Cutoff value

Accuracy (%) PSP-P patients with O2 level vs. PD patients

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Cutoff value Sensitivity (%) Specificity (%) PPV (%) NPV (%)

100

84.9

94.3

63.6

86.4

90.0

100

81.9

95.8

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Accuracy (%)

73.7

Abbreviations: PSP-P = progressive supranuclear palsy-parkinsonism; O1 level = vertical supranuclear gaze palsy; O2 level = slowness of vertical saccades; PD = Parkinson’s disease; MRPI = magnetic resonance parkinsonism index; PPV = positive predictive value; NPV = negative predictive value. a

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Optimal cutoff values were determined by using receiver operating characteristic curve analysis.

McNemar’s test showed no significant differences (p = 1) in comparing the diagnostic accuracies of MRPI vs. MRPI 2.0 to

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differentiate patients with PSP-P with O1 level from patients with PD whereas McNemar’s test showed significant differences (p = 0.004) in comparing the diagnostic accuracies of MRPI vs. MRPI 2.0 to differentiate patients with PSP-P with O2 level from patients with PD.

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ACCEPTED MANUSCRIPT Highlights 1. Distinguishing PSP-P from PD is challenging in the early stages of the disease 2. Few data exist on the usefulness of MRPI for diagnosing PSP-P patients 3. MRPI 2.0 is a new version of MRPI which includes the 3rd ventricular width 4. MRPI 2.0 accurately differentiated patients with PSP-P from those with PD

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5. MRPI 2.0 accurately diagnosed PSP-P in the absence of vertical ocular palsy