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INTRODUCTION: Postural instability (PI) is a common disabling symptom in Parkinson's disease (PD) patients, but the brain alterations underlying this sign are not fully understood yet. This study aimed to investigate the association between PI and callosal damage in PD and progressive supranuclear palsy (PSP) patients, using multimodal MR imaging. METHODS: One-hundred and two PD patients stratified according to the presence/absence of PI (PD-steady N=58; PD-unsteady N=44), 69 PSP patients, and 38 healthy controls (HC) underwent structural and diffusion 3T brain MRI. Thickness, fractional anisotropy (FA) and mean diffusivity (MD) were calculated over 50 equidistant points covering the whole midsagittal profile of the corpus callosum (CC) and compared among groups. Associations between imaging metrics and postural instability score were investigated using linear regression. RESULTS: Both PSP and PD-unsteady patient groups showed CC involvement in comparison with HC, while no difference was found between PD-steady patients and controls. The CC damage was more severe and widespread in PSP than in PD patients. The CC genu was the regions most damaged in PD-unsteady patients compared with PD-steady patients, showing significant microstructural alterations of MD and FA metrics. Linear regression analysis pointed at the MD in the CC genu as the main contributor to PI among the considered MRI metrics. CONCLUSION: This study identified callosal microstructural alterations associated with PI in unsteady PD and PSP patients, which provide new insights on PI pathophysiology and might serve as imaging biomarkers for assessing postural instability progression and treatment response.
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BACKGROUND: Differentiating Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) from PSP-Parkinsonism (PSP-P) may be extremely challenging. In this study, we aimed to distinguish these two PSP phenotypes using MRI structural data. METHODS: Sixty-two PSP-RS, 40 PSP-P patients and 33 control subjects were enrolled. All patients underwent brain 3 T-MRI; cortical thickness and cortical/subcortical volumes were extracted using Freesurfer on T1-weighted images. We calculated the automated MR Parkinsonism Index (MRPI) and its second version including also the third ventricle width (MRPI 2.0) and tested their classification performance. We also employed a Machine learning (ML) classification approach using two decision tree-based algorithms (eXtreme Gradient Boosting [XGBoost] and Random Forest) with different combinations of structural MRI data in differentiating between PSP phenotypes. RESULTS: MRPI and MRPI 2.0 had AUC of 0.88 and 0.81, respectively, in differentiating PSP-RS from PSP-P. ML models demonstrated that the combination of MRPI and volumetric/thickness data was more powerful than each feature alone. The two ML algorithms showed comparable results, and the best ML model in differentiating between PSP phenotypes used XGBoost with a combination of MRPI, cortical thickness and subcortical volumes (AUC 0.93 ± 0.04). Similar performance (AUC 0.93 ± 0.06) was also obtained in a sub-cohort of 59 early PSP patients. CONCLUSION: The combined use of MRPI and volumetric/thickness data was more accurate than each MRI feature alone in differentiating between PSP-RS and PSP-P. Our study supports the use of structural MRI to improve the early differential diagnosis between common PSP phenotypes, which may be relevant for prognostic implications and patient inclusion in clinical trials.
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Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Humanos , Transtornos Parkinsonianos/diagnóstico , Imageamento por Ressonância Magnética/métodos , Paralisia Supranuclear Progressiva/diagnóstico , Neuroimagem , Diagnóstico DiferencialRESUMO
Recently, a novel pathogenic variant in Annexin A1 protein (c.4G > A, p.Ala2Thr) has been identified in an Iranian consanguineous family with autosomal recessive parkinsonism. The deficiencies of ANXA1 could lead to extracellular SNCA accumulation, defects in intracellular signaling pathways and synaptic plasticity causing parkinsonism. The aim of this study was to identify rare ANXA1 variants in 95 early-onset PD patients from South Italy. Sequencing analysis of ANXA1 gene revealed only 2 synonymous variants in PD patients (rs1050305, rs149033255). Therefore, we conclude that the recently published ANXA1 mutation is not a common cause of EOPD in Southern Italy.
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Transtornos Parkinsonianos , Humanos , Idade de Início , Irã (Geográfico) , Itália , Mutação/genética , Transtornos Parkinsonianos/genéticaRESUMO
The clinical differential diagnosis between Parkinson's disease (PD) and progressive supranuclear palsy (PSP) is often challenging. The description of milder PSP phenotypes strongly resembling PD, such as PSP-Parkinsonism, further increased the diagnostic challenge and the need for reliable neuroimaging biomarkers to enhance the diagnostic certainty. This review aims to summarize the contribution of a relatively simple and widely available imaging technique such as MR planimetry in the differential diagnosis between PD and PSP, focusing on the recent advancements in this field. The development of accurate MR planimetric biomarkers, together with the implementation of automated algorithms, led to robust and objective measures for the differential diagnosis of PSP and PD at the individual level. Evidence from longitudinal studies also suggests a role of MR planimetry in predicting the development of the PSP clinical signs, allowing to identify PSP patients before they meet diagnostic criteria when their clinical phenotype can be indistinguishable from PD. Finally, promising evidence exists on the possible association between MR planimetric measures and the underlying pathology, with important implications for trials with new disease-modifying target therapies.
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INTRODUCTION: Progressive supranuclear palsy (PSP) patients show reduced amplitude and velocity of vertical saccades, but saccadic abnormalities have also been reported in Parkinson's disease (PD). We investigated amplitude and velocity of vertical saccades in PSP and PD patients, to establish the best video-oculographic (VOG) parameters for PSP diagnosis. METHODS: Fifty-one PSP patients, 113 PD patients and 40 controls were enrolled. The diagnosis was performed on a clinico-radiological basis (MR Parkinsonism index [MRPI] and MRPI 2.0). We used VOG to assess the diagnostic performances of saccadic amplitude, peak velocity, and their product (AxV) in upward or downward direction and in vertical gaze (upward and downward averaged) in distinguishing PSP from PD patients. The vestibulo-ocular reflex, necessary to establish the supranuclear nature of ocular dysfunction, was evaluated clinically. RESULTS: PSP patients showed significantly reduced amplitude and peak velocity of ocular saccades in upward and downward directions compared to PD and healthy subjects. In PD patients, upward gaze amplitude was lower than in controls. In vertical gaze, the peak velocity showed 99.1% specificity and 54.7% sensitivity for PSP classification. The AxV product showed high specificity (94.7%) and sensitivity (84.3%) and yielded higher accuracy (91.5%) than velocity and amplitude used alone in distinguishing PSP from PD. CONCLUSION: Our study demonstrates that the peak velocity of vertical saccades was a very low sensitive parameter and cannot be used alone for PSP diagnosis. A new index combining amplitude and peak velocity in vertical gaze seems the most suitable video-oculographic biomarker for differentiating PSP from PD and controls.
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Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Biomarcadores , Humanos , Imageamento por Ressonância Magnética , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Paralisia Supranuclear Progressiva/diagnósticoRESUMO
BACKGROUND: Hepatic encephalopathy is defined as a spectrum of neuropsychiatric disorders in patients with liver dysfunction, usually cirrhosis, after exclusion of brain disease. This study reports the role of manganese in brain alterations and therefore in clinical manifestations of hepatic encephalopathy. CASE PRESENTATION: Male patient, 67 years old, suffering from alcoholic liver cirrhosis and two previous episodes of hepatic encephalopathy, developed drowsiness, asterixis, amnesia, disorientation in time and space, and psychomotor retardation. Brain MRI without contrast showed: initial signs of cerebral atrophy, a hyperintense signal of globi pallidi and bilateral substantia nigra. The hyperintense signal of globi pallidi is the result of manganese deposition in the brain. CONCLUSION: The case report presented supports the data reported in the literature indicating that the increase in plasma manganese levels in subjects with liver dysfunction is correlated with the onset of extrapyramidal symptoms.
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BACKGROUND: Differentiating progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) is clinically challenging. OBJECTIVE: This study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP-P from PD and to validate its diagnostic performance in two large independent cohorts. METHODS: We enrolled 676 participants: a training cohort (n = 346; 43 PSP-P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n = 330; 62 PSP-P, 171 PD, and 97 control subjects) from an international research group. We developed a new in-house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP-P from PD and control subjects in both cohorts using receiver operating characteristic curves. RESULTS: The automated MRPI 2.0 showed excellent performance in differentiating patients with PSP-P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC] = 0.93 [95% confidence interval, 0.89-0.98] and AUC = 0.97 [0.93-1.00], respectively) and in the international testing cohort (PSP-P versus PD, AUC = 0.92 [0.87-0.97]; PSP-P versus controls, AUC = 0.94 [0.90-0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP-P and PD in the early stage of the diseases (AUC = 0.91 [0.84-0.97]). A strong correlation (r = 0.91, P < 0.001) was found between automated and manual MRPI 2.0 values. CONCLUSIONS: Our study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP-P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP-P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Paralisia/diagnóstico , Doença de Parkinson/diagnóstico , Doença de Parkinson/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico por imagem , Paralisia Supranuclear Progressiva/diagnóstico por imagemRESUMO
Exanucleotide expansions in C9orf72 gene have been described as potential risk factor in some patients with Multiple system atrophy (MSA) and other forms of atypical parkinsonism. The goal of our study was to extend the knowledge on the involvement of C9orf72 in MSA studying a cohort of 100 patients from Italy. We identified 2 heterozygous patients in the pathological range (> 30 repeats) and 4 heterozygous patients for expansions in the premutation range (20 -30 repeats). Our findings strengthen the previously hypothesized role for this gene as a risk factor for MSA and raise the possibility of a more complex and still unknown involvement of this gene in the heterogeneity of MSA.
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Esclerose Lateral Amiotrófica , Proteína C9orf72 , Atrofia de Múltiplos Sistemas , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Estudos de Coortes , Expansão das Repetições de DNA/genética , Humanos , Atrofia de Múltiplos Sistemas/genética , Proteínas/genéticaRESUMO
Deep grey nuclei of the human brain accumulate minerals both in aging and in several neurodegenerative diseases. Mineral deposition produces a shortening of the transverse relaxation time which causes hypointensity on magnetic resonance (MR) imaging. The physician often has difficulties in determining whether the incidental hypointensity of grey nuclei seen on MR images is related to aging or neurodegenerative pathology. We investigated the hypointensity patterns in globus pallidus, putamen, caudate nucleus, thalamus and dentate nucleus of 217 healthy subjects (ages, 20-79 years; men/women, 104/113) using 3T MR imaging. Hypointensity was detected more frequently in globus pallidus (35.5%) than in dentate nucleus (32.7%) and putamen (7.8%). A consistent effect of aging on hypointensity (p < 0.001) of these grey nuclei was evident. Putaminal hypointensity appeared only in elderly subjects whereas we did not find hypointensity in the caudate nucleus and thalamus of any subject. In conclusion, the evidence of hypointensity in the caudate nucleus and thalamus at any age or hypointensity in the putamen seen in young subjects should prompt the clinician to consider a neurodegenerative disease.
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Doenças Neurodegenerativas , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Feminino , Substância Cinzenta , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico por imagem , Putamen/diagnóstico por imagem , Adulto JovemRESUMO
BACKGROUND: Progressive supranuclear palsy (PSP) patients can show ventricular enlargement mimicking normal pressure hydrocephalus (NPH). The aim of this study was to distinguish PSP patients with marked ventricular dilatation (PSP-vd) from those with normal ventricular system and to evaluate the coexistence of NPH in PSP-vd patients. METHODS: One hundred three probable PSP patients, 18 definite NPH patients, and 41 control subjects were enrolled in the study. Evans index (EI) > 0.32 associated with callosal angle (CA) < 100° was used to identify PSP-vd patients. Automated ventricular volumetry (AVV) and Magnetic Resonance Hydrocephalic Index (MRHI) were performed on T1-weighted MR images to evaluate the presence of NPH in PSP-vd patients. RESULTS: Twelve (11.6%) out of 103 PSP patients had both abnormal EI and CA values (PSP-vd). In two of these 12 patients, AVV and MRHI values suggested PSP + NPH. In the remaining 10 PSP-vd patients, AVV and MRHI values were higher than PSP patients with normal ventricular system and controls, but lower than PSP + NPH and NPH patients, suggesting a non-hydrocephalic ventricular enlargement. DISCUSSION: Our study provides evidence that the combination of EI and CA biomarkers allowed to identify PSP patients with marked ventricular dilatation mimicking NPH. Only a few of these patients had PSP + NPH. Recognition of these PSP patients with enlarged ventricles can positively impact the care of this disease, helping clinicians to identify patients with PSP + NPH who could benefit from shunt procedure and avoid surgery in those with enlarged ventricles without NPH.
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Hidrocefalia de Pressão Normal , Paralisia Supranuclear Progressiva , Corpo Caloso/patologia , Dilatação , Humanos , Hidrocefalia de Pressão Normal/complicações , Hidrocefalia de Pressão Normal/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/diagnóstico por imagemRESUMO
Introduction: Hyper-religiosity has been reported in patients affected by frontotemporal dementia (FTD) with asymmetrical, predominantly right-sided frontotemporal atrophy. Case report: We report a FTD patient carrying a double genetic variant (p.Cys139Arg and c.*78C > T) in the progranulin (GRN) gene who showed an unusual clinical phenotype characterized by hyper-religiosity behavior and visual hallucinations with exclusively religious content. Noteworthy, this patient exhibited a slow clinical and radiological rate of disease progression and a predominantly left-sided frontotemporal atrophy. Discussion and conclusion: The simultaneous presence of these GRN variants in our FTD patient with predominant atrophy in the left (dominant) hemisphere could determine the unusual phenotype with hyper-religiosity and visual hallucinations with exclusively religious content and influence the slow rate of disease progression.
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Esclerose Lateral Amiotrófica , Demência Frontotemporal , Doença de Pick , Demência Frontotemporal/complicações , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Alucinações/genética , Humanos , Mutação , Progranulinas/genéticaAssuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson/genética , ATPases Translocadoras de Prótons , Adolescente , Adulto , Idoso , Análise Mutacional de DNA , Humanos , Itália , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/genética , Mutação/genética , ATPases Translocadoras de Prótons/genética , ATPases Translocadoras de Prótons/metabolismo , Adulto JovemRESUMO
BACKGROUND: Microstructural alterations of corticospinal tract (CST) have been found in idiopathic normal pressure hydrocephalus (iNPH). No study, however, investigated the effect of ventricular dilatation on CST in Progressive Supranuclear Palsy (PSP). OBJECTIVE: The aim of this study was to investigate CST diffusion profile in a large cohort of PSP patients with and without ventricular dilatation. METHODS: Twenty-three iNPH patients, 87 PSP patients and 26 controls were enrolled. Evans index (EI) and ventricular volume (VV) were measured in all patients. CST tractography was performed to calculate FA, MD, AxD and RD in six different anatomical regions: medulla oblungata (MO), pons (P), cerebral peduncle (CP), posterior limb of internal capsule (PLIC), corona radiata (CR), subcortical white matter (SWM). ANCOVA was used for comparing CST diffusion profiles between the groups and association between CST microstructural metrics and measures of ventricular dilatation (EI and VV) was assessed. RESULTS: Thirty-three PSP patients had ventricular dilatation (EI > 0.30, PSP-vd) while 54 PSP patients had normal ventricular system (EI ≤ 0.30, PSP-wvd). iNPH patients had the most marked FA and AxD increase in PLIC and CR of CST followed by PSP-vd, PSP-wvd and controls; RD was altered only in iNPH. A strong correlation was found between CST diffusion metrics and EI or VV. CONCLUSIONS: Our findings confirm the microstructural changes of CST in iNPH patients and demonstrate for the first time similar alterations in PSP-vd patients, suggesting a crucial role of ventricular dilatation in the mechanical compression of CST.
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Tratos Piramidais , Paralisia Supranuclear Progressiva , Imagem de Tensor de Difusão , Dilatação , Humanos , Cápsula Interna , Tratos Piramidais/diagnóstico por imagemRESUMO
Recently, the LRP10 gene has been associated with Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). The aim of the present study was to evaluate the presence of mutations of the LRP10 gene in patients with PD or DLB from Southern Italy. Sequencing analysis revealed only 2 missense and 3 synonymous variants in patients and control subjects and a rare variant p.L622F in a PD case. These results suggest that LRP10 mutations are not a frequent cause of PD and DLB in Southern Italy.
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Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Parkinson , Humanos , Itália , Doença por Corpos de Lewy/genética , Mutação/genética , Doença de Parkinson/genéticaRESUMO
Progressive supranuclear palsy (PSP) is a rare, rapidly progressive neurodegenerative disease. Richardson's syndrome (PSP-RS) and predominant parkinsonism (PSP-P) are characterized by wide range of cognitive and behavioural disturbances, but these variants show similar cognitive pattern of alterations, leading difficult differential diagnosis. For this reason, we explored with an Artificial Intelligence approach, whether cognitive impairment could differentiate the phenotypes. Forty Parkinson's disease (PD) patients, 25 PSP-P, 40 PSP-RS, and 34 controls were enrolled following the consensus criteria diagnosis. Participants were evaluated with neuropsychological battery for cognitive domains. Random Forest models were used for exploring the discriminant power of the cognitive tests in distinguishing among the four groups. The classifiers for distinguishing diseases from controls reached high accuracies (86% for PD, 95% for PSP-P, 99% for PSP-RS). Regarding the differential diagnosis, PD was discriminated from PSP-P with 91% (important variables: HAMA, MMSE, JLO, RAVLT_I, BDI-II) and from PSP-RS with 92% (important variables: COWAT, JLO, FAB). PSP-P was distinguished from PSP-RS with 84% (important variables: JLO, WCFST, RAVLT_I, Digit span_F). This study revealed that PSP-P, PSP-RS and PD had peculiar cognitive deficits compared with healthy subjects, from which they were discriminated with optimal accuracies. Moreover, high accuracies were reached also in differential diagnosis. Most importantly, Machine Learning resulted to be useful to the clinical neuropsychologist in choosing the most appropriate neuropsychological tests for the cognitive evaluation of PSP patients.
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Doenças Neurodegenerativas , Paralisia Supranuclear Progressiva , Inteligência Artificial , Humanos , Aprendizado de Máquina , Testes Neuropsicológicos , Fenótipo , Paralisia Supranuclear Progressiva/diagnósticoRESUMO
BACKGROUND: Enlargement of the third ventricle has been reported in atypical parkinsonism. We investigated whether the measurement of third ventricle width could distinguish Parkinson's disease (PD) from progressive supranuclear palsy (PSP). METHODS: We assessed a new MR T1-weighted measurement (third ventricle width/internal skull diameter) in a training cohort of 268 participants (98 PD, 73 PSP, 98 controls from our center) and in a testing cohort of 291 participants (82 de novo PD patients and 133 controls from the Parkinson's Progression Markers Initiative, 76 early-stage PSP from an international research group). PD diagnosis was confirmed after a 4-year follow-up. Diagnostic performance of the third ventricle/internal skull diameter was assessed using receiver operating characteristic curve with bootstrapping; the area under the curve of the training cohort was compared with the area under the curve of the testing cohort using the De Long test. RESULTS: In both cohorts, third ventricle/internal skull diameter values did not differ between PD and controls but were significantly lower in PD than in PSP patients (P < 0.0001). In PD, third ventricle/internal skull diameter values did not change significantly between baseline and follow-up evaluation. Receiver operating characteristic analysis accurately differentiated PD from PSP in the training cohort (area under the curve, 0.94; 95% CI, 91.1-97.6; cutoff, 5.72) and in the testing cohort (area under the curve, 0.91; 95% CI, 87.0-97.0; cutoff,: 5.88), validating the generalizability of the results. CONCLUSION: Our study provides a new reliable and validated MRI measurement for the early differentiation of PD and PSP. The simplicity and generalizability of this biomarker make it suitable for routine clinical practice and for selection of patients in clinical trials worldwide. © 2020 International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico , Paralisia Supranuclear Progressiva/diagnóstico por imagemRESUMO
BACKGROUND: Idiopathic normal pressure hydrocephalus and PSP share several clinical and radiological features, making differential diagnosis, at times, challenging. OBJECTIVES: To differentiate idiopathic normal pressure hydrocephalus from PSP using MR volumetric and linear measurements. METHODS: Twenty-seven idiopathic normal pressure hydrocephalus patients, 103 probable PSP patients, and 43 control subjects were consecutively enrolled. Automated ventricular volumetry was performed using Freesurfer 6 on MR T1 -weighted images. Linear measurements, such as callosal angle and a new measure, termed MR Hydrocephalic Index, were calculated on MR T1 -weighted images. Receiver operating characteristic analyses were used for differentiating between patient groups. Generalizability and reproducibility of the results were validated, dividing each participant group in two cohorts used as training and testing subsets. RESULTS: Ventricular volumes and linear measurements (callosal angle and Magnetic Resonance Hydrocephalic Index) revealed greater ventricular enlargement in patients with idiopathic normal pressure hydrocephalus than in PSP patients and controls. PSP patients had ventricular volume larger than controls. Automated ventricular volumetry and Magnetic Resonance Hydrocephalic Index were the most accurate measures (98.5%) in differentiating patients with idiopathic normal pressure hydrocephalus from PSP patients, whereas callosal angle misclassified several PSP patients and showed low positive predictive value (70.0%) in differentiating between these two diseases. All measurements accurately differentiated idiopathic normal pressure hydrocephalus patients from controls. Accuracy values obtained in the training set (automated ventricular volumetry, 98.4%; Magnetic Resonance Hydrocephalic Index, 98.4%; callosal angle, 87.5%) were confirmed in the testing set. CONCLUSIONS: Our study demonstrates that AVV and Magnetic Resonance Hydrocephalic Index were the most accurate measures for differentiation between idiopathic normal pressure hydrocephalus and PSP patients. Magnetic Resonance Hydrocephalic Index is easy to measure and can be used in clinical practice to prevent misdiagnosis and ineffective shunt procedures in idiopathic normal pressure hydrocephalus mimics. © 2020 International Parkinson and Movement Disorder Society.