Progressive Supranuclear Palsy Parkinsonism Research Articles

Reply: MRI measurements of brain stem structures in patients with Richardson's syndrome, progressive supranuclear palsy-parkinsonism, and Parkinson's disease

Movement DisordersVolume 26, Issue 8 p. 1575-1576 Letter to the Editor Reply: MRI measurements of brain stem structures in patients with Richardson's syndrome, progressive supranuclear palsy–parkinsonism, and Parkinson's disease†‡§ Federica Agosta MD, Federica Agosta MD Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, ItalySearch for more papers by this authorGiulia Longoni MD, Giulia Longoni MD Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, ItalySearch for more papers by this authorVladimir S. Kostić MD, Vladimir S. Kostić MD Department of Neurology, School of Medicine, University of Belgrade, Belgrade, SerbiaSearch for more papers by this authorTanja Stojković MD, Tanja Stojković MD Department of Neurology, School of Medicine, University of Belgrade, Belgrade, SerbiaSearch for more papers by this authorElisabetta Pagani MSc, Elisabetta Pagani MSc Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, ItalySearch for more papers by this authorTatjana Stošić-Opinć MD, Tatjana Stošić-Opinć MD Department of Neurology, School of Medicine, University of Belgrade, Belgrade, SerbiaSearch for more papers by this authorMassimo Filippi MD, Corresponding Author Massimo Filippi MD m.filippi@hsr.it Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, ItalyNeuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University, Ospedale San Raffaele, Milan, ItalySearch for more papers by this author Federica Agosta MD, Federica Agosta MD Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, ItalySearch for more papers by this authorGiulia Longoni MD, Giulia Longoni MD Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, ItalySearch for more papers by this authorVladimir S. Kostić MD, Vladimir S. Kostić MD Department of Neurology, School of Medicine, University of Belgrade, Belgrade, SerbiaSearch for more papers by this authorTanja Stojković MD, Tanja Stojković MD Department of Neurology, School of Medicine, University of Belgrade, Belgrade, SerbiaSearch for more papers by this authorElisabetta Pagani MSc, Elisabetta Pagani MSc Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, ItalySearch for more papers by this authorTatjana Stošić-Opinć MD, Tatjana Stošić-Opinć MD Department of Neurology, School of Medicine, University of Belgrade, Belgrade, SerbiaSearch for more papers by this authorMassimo Filippi MD, Corresponding Author Massimo Filippi MD m.filippi@hsr.it Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, ItalyNeuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University, Ospedale San Raffaele, Milan, ItalySearch for more papers by this author First published: 05 April 2011 https://doi.org/10.1002/mds.23702 † Funding agencies: This project was partly supported by a grant from the Ministry of Science and Technology of the Republic of Serbia (Grant 145057). ‡ Relevant conflicts of interest/financial disclosures: Nothing to report. § Full financial disclosures and author roles may be found in the online version of this article. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume26, Issue8July 2011Pages 1575-1576 RelatedInformation

In vivo comparison of Richardson’s syndrome and progressive supranuclear palsy-parkinsonism

Richardson's syndrome (RS) and progressive supranuclear palsy-parkinsonism (PSP-P) are the most common subtypes of PSP. Post-mortem data suggests that the clinical presentation of the two subtypes differs especially in the first 2years of disease and then converges. This hypothesis has, to our knowledge, never been confirmed in a living cohort. Medical history was used to define subtypes retrospectively in 23 consecutive PSP patients from our outpatient clinic specialized in movement disorders. 14 patients suffered from RS, and 9 from PSP-P. Using a prospective cross-sectional approach, clinical, cognitive, behavioral, speech and biochemical (cerebrospinal fluid tau levels) features were compared. RS patients showed shorter time from disease onset to diagnosis and more neuropsychological and neurobehavioral deficits than PSP-P patients, but differed not significantly with regard to clinical and biochemical features. RS and PSP-P show considerable symptoms overlap during the disease course when using routine assessments, with persisting differences regarding non-motor symptoms. Shorter disease duration of the comparably affected RS patients indicates that this subtype has an accelerated disease progression at early disease stages.

MRI measurements of brainstem structures in patients with Richardson's syndrome, progressive supranuclear palsy-parkinsonism, and Parkinson's disease

We investigated the diagnostic accuracy of brainstem MRI measurements in patients with different progressive supranuclear palsy (PSP) syndromes and Parkinson's disease (PD). Using 3D T1-weighted images, midbrain, and pons areas, as well as superior (SCP) and middle cerebellar peduncle (MCP) widths were measured in 10 patients with Richardson's syndrome (PSP-RS), 10 patients with PSP-parkinsonism (PSP-P), 25 patients with PD, and 24 healthy controls. The ratio between pons and midbrain areas (pons/midbrain), that between MCP and SCP widths (MCP/SCP), and the MR parkinsonism index ([pons/midbrain]*[MCP/SCP]) were calculated. The pons/midbrain and the MR parkinsonism index allowed to differentiate PSP-RS from PD with high sensitivity (90%, 100%), specificity (96%, 92%), and accuracy (94%, 97%). Only the pons/midbrain was found to distinguish PSP-P from PD, but with a lower diagnostic accuracy (sensitivity = 60%, specificity = 96%, accuracy = 86%). Compared to PSP-RS, PSP-P experience a relatively less severe involvement of infratentorial brain. The pons/midbrain looks as a promising measure in the differentiation of individual PSP-P from PD patients.

Cortical atrophy differentiates Richardson's syndrome from the parkinsonian form of progressive supranuclear palsy

To determine whether brain atrophy differs between the two subtypes of progressive supranuclear palsy (PSP), Richardson's syndrome (PSP-RS), and PSP parkinsonism (PSP-P), and whether such atrophy directly relates to clinical deficits and the severity of tau deposition. We compared 24 pathologically confirmed PSP cases (17 PSP-RS and 7 PSP-P) with 22 controls from a Sydney brain donor program. Volume loss was analyzed in 29 anatomically discrete brain regions using a validated point-counting technique, and tau-immunoreactive neurons, astrocytes and oligodendrocytes/threads semiquantified. Correlations between the two pathological measures and the presence or absence of cardinal PSP symptoms were investigated. Cortical atrophy was more severe in PSP-RS than PSP-P and affected more frontal lobe regions (frontal pole, inferior frontal gyrus). The supramarginal gyrus was atrophic in both subtypes. Additionally, atrophy of the internal globus pallidus, amygdala, and thalamus was more severe in PSP-RS. As expected, more severe frontal lobe tau pathology differentiated PSP-RS from PSP-P. No correlations were found between the degree of atrophy and severity of tau pathology in any region assessed, or between the severity of atrophy or tau pathology and the presence or absence of cardinal PSP symptoms. Our study shows that thalamocortical atrophy is a defining feature of PSP-RS, but this atrophy does not correlate with the presence of any specific cardinal clinical feature. Interestingly, there is a disassociation between tau pathology and atrophy in the brain regions affected in PSP-RS that requires further investigation.

Preliminary studies of differential impairments of the dopaminergic system in subtypes of progressive supranuclear palsy

Richardson's syndrome (RS) and progressive supranuclear palsy-parkinsonism (PSP-P) are the most common subtypes of PSP syndrome. The clinical features, responses to levodopa, and progression are relatively different but overlap. Determining whether combined molecular imaging studies of dopamine transporter and D2 receptor are helpful for further differentiation of these two subtypes is important. Ten patients with PSP (six suffering from RS and four from PSP-P) were studied. We also enrolled 10 patients with Parkinson's disease (PD) as disease control and seven healthy individuals as normal controls. Each individual underwent two sets of single photon emission computer tomography imaging, [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2',S2,S2']oxo[1R-(exo-exo)])-[Tc] Technetium (Tc-TRODAT-1) dopamine transporter (DAT) and I-iodobenzamide D2 receptor. The specific uptake ratio was calculated as (basal ganglia counts-occipital cortex counts)/occipital cortex counts. In DAT scan, the mean striatal uptake was reduced in the RS group compared with that in the PSP-P group, although it did not reach statistical significance. The putamen-to-caudate nucleus ratios were significantly different between PD and all PSP patients (P<0.001), but no difference in putamen-to-caudate ratios was found between the RS and PSP-P groups. In the I iodobenzamide scan, striatal uptake was significantly reduced in the RS group (-22.62%, P=0.022); on the contrary, it was mildly increased in the PSP-P group. The studies showed different alterations of DAT and D2 receptor function between the RS and PSP-P groups. Different DAT imaging might be helpful to distinguish PSP-P from PD in the early stage.

The in vivo distribution of brain tissue loss in Richardson’s syndrome and PSP‐parkinsonism: a VBM‐DARTEL study

In this study, we wished to test, using magnetic resonance imaging and voxel-based morphometry (VBM), whether specific cortical and subcortical patterns of brain grey (GM) and white matter (WM) tissue loss can be detected in patients with Richardson's syndrome (PSP-RS) and progressive supranuclear palsy-parkinsonism (PSP-P), and possibly account for their clinical heterogeneity. Twenty patients with PSP, classified as PSP-RS (10 patients) or PSP-P (10 patients), and 24 healthy controls were studied. The Statistical Parametric Mapping (SPM5) and the Diffeomorphic Anatomical Registration using Exponentiated Lie algebra method were used to perform a VBM analysis. Compared with controls, both patient groups showed GM loss in the central midbrain, cerebellar lobes, caudate nuclei, frontotemporal cortices and right hippocampus. WM loss was detected in both conditions in the midbrain, left superior cerebellar peduncle, internal capsulae, and left premotor and bilateral prefrontal regions. Compared with PSP-P, patients with PSP-RS showed additional regions of GM loss in the midbrain, left cerebellar lobe and dentate nuclei. PSP-RS was also associated with a more severe WM loss in the midbrain, internal capsulae, and orbitofrontal, prefrontal and precentral/premotor regions, bilaterally. Patients with PSP-P showed a more pronounced GM loss only in the frontal cortex, bilaterally. This study shows that, albeit the overall pattern of brain atrophy associated with PSP appears remarkably consistent across the spectrum of clinical features recorded in life, major anatomical differences between these two conditions do exist. Such a different topographical distribution of tissue damage may account for the clinical differences between PSP-RS and PSP-P.

What features improve the accuracy of the clinical diagnosis of progressive supranuclear palsy‐parkinsonism (PSP‐P)?

Progressive supranuclear palsy-parkinsonism (PSP-P) is a primary tauopathy characterised by neurofibrillary degeneration, which is frequently mistaken for Parkinson's disease (PD), multiple system atrophy (MSA), and vascular parkinsonism (VP) at presentation. The aim of this study was to identify particular clinical features (green flags) that may be helpful in differentiating PSP-P from these other disorders. We identified 37 patients with PSP-P from 726 patients archived at the Queen Square Brain Bank. Using a retrospective case notes review the clinical features were compared between the PSP-P group and Lewy body associated parkinsonism (PD, n = 444 and dementia with Lewy bodies (DLB), n = 46), MSA (n = 90), and VP (n = 19), using the chi(2)-test for proportions for a two-by-two contingency table. The sensitivity, specificity, and positive predictive values (PPV) and negative predictive values (NPV) were calculated for individual clinical features. A specificity of >0.85 or a PPV of >0.85 were considered reliable discriminators. No clinical features were predictive of PSP-P, but late drug induced dyskinesias (specificity 0.92, PPV 0.99), late autonomic dysfunction (specificity 0.94, PPV 0.99) and any visual hallucinations (specificity 0.94, PPV 0.99) were better in distinguishing PD and PSP-P than predicted using operational diagnostic criteria for PD. PSP-P shares many clinical features with PD and DLB, MSA and VP, but visual hallucinations, drug induced dyskinesias and autonomic dysfunction are very uncommon and may be helpful exclusion criteria.

EVOLUTION OF OCULOMOTOR AND CLINICAL FINDINGS IN AUTOPSY-PROVEN RICHARDSON SYNDROME

Progressive supranuclear palsy (PSP) is a parkinsonian disorder characterized by early, frequent falls, dysphagia, and vertical gaze disturbance.1,2 PSP has recently been split into 3 entities—Richardson syndrome (RS), progressive supranuclear palsy–parkinsonism (PSP-P), and pure akinesia—which correlate with the amount and distribution of tau-protein load in the brain at autopsy.3,4 We report an autopsy-proven case of RS who presented with atypical features; however, slow vertical saccades were evident at presentation. ### Case reports. A 49-year-old man presented complaining of binocular, horizontal diplopia for 1 year. He also reported difficulty “following a sentence” during reading. Because of memory problems, he had relinquished control of family finances to his wife. He denied falls but had stopped playing tennis because he “could not keep up.” He had a flat affect and Mini-Mental State Examination score of 29/30. Corrected visual acuity was 20/20 OD and 20/25 OS; eyelids and pupils were normal. Range of eye movements was full, but with concomitant 6-prism diopter esotropia during distance viewing (divergence insufficiency); convergence was also impaired. Voluntary saccades were slow, especially vertically, but full in range. Smooth pursuit and vestibular eye movements appeared normal. Tendon reflexes and jaw jerk were increased. He could not perform the Luria 3-step test; palmomental reflex was prominent. He could clap exactly 3 times. Neuropsychological testing suggested frontal lobe dysexecutive syndrome with a subcortical component. His mother had developed dementia at age 70, attributed to Alzheimer disease, and apparently showed similar clinical features. Over the next 2 years, he developed greater hyperreflexia with ankle clonus, cervical dystonia, jaw-closing oromandibular dystonia, generalized akinesia, postural instability, visuospatial dysfunction, and inappropriate emotional expression. Repeat neuropsychological testing revealed a global …

Subthalamic stimulation improves levodopa responsive symptoms in a case of progressive supranuclear palsy

A case is described of a patient with levodopa responsive parkinsonism, dyskinesia, and off periods who underwent bilateral deep brain stimulation of the subthalamic nuclei (DBS-STN) with good result. As the disease progressed, the patient fit diagnostic criteria for progressive supranuclear palsy parkinsonism (PSP-P). Benefit of DBS for the parkinsonian phenomena is still apparent 4 years later. That DBS-STN provided targeted symptom relief in this unusual patient suggests that the parkinsonism of PSP-P and that of Parkinson's disease (PD) may share a common pathophysiologic mechanism. The presence of dystonic features in this illness raises the possibility that the globus pallidus might also have been an effective target.

Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome

Clinical syndromes associated with progressive supranuclear palsy-tau pathology now include progressive supranuclear palsy-parkinsonism (PSP-P), in addition to classic Richardson's syndrome (RS) and pure akinesia with gait freezing (PAGF). Although pathological heterogeneity of progressive supranuclear palsy (PSP) has also been established, attempts to correlate this with clinical findings have only rarely provided conclusive results. The aim of this study was to investigate whether regional variations in the types of tau lesions or differences in overall tau load may explain the clinical differences between the RS, PSP-P and PAGF. Quantitative tau pathology assessment was performed in 17 brain regions in 42 cases of pathologically diagnosed PSP (22 RS, 14 PSP-P and 6 PAGF). Neurofibrillary tangles, tufted astrocytes, coiled bodies and thread pathology were quantitated and a grading system was developed separately for each region. Using these grades the overall tau load was calculated in each case. To establish a simplified system for grading the severity of tau pathology, all data were explored to identify the minimum number of regions that satisfactorily summarized the overall tau severity. The subthalamic nucleus, substantia nigra and globus pallidus were consistently the regions most severely affected by tau pathology. The mean severity in all regions of the RS group was higher than in PSP-P and PAGF, and the overall tau load was significantly higher in RS than in PSP-P (P = 0.002). Using only the grade of coiled body + thread lesions in the substantia nigra, caudate and dentate nucleus, a reliable and repeatable 12-tiered grading system was established (PSP-tau score: 0, mild tau pathology, restricted distribution; >7, severe, widespread tau pathology). PSP-tau score was negatively correlated with disease duration (Spearman's rho -0.36, P = 0.028) and time from disease onset to first fall (Spearman's rho -0.49, P = 0.003). The PSP-tau score in PSP-P (median 3, range 0-5) was significantly lower than in RS (median 5, range 2-10, Mann-Whitney U, P < 0.001). The two cases carrying the tau-H2 protective allele had the two lowest PSP-tau scores. We have identified significant pathological differences between the major clinical syndromes associated with PSP-tau pathology and the restricted, mild tau pathology in PSP-P supports its clinical distinction from RS. The grading system we have developed provides an easy-to-use and sensitive tool for the morphological assessment of PSP-tau pathology and allows for consideration of the clinical diversity that is known to occur in PSP.

Commentary on: Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP–parkinsonism, by D. Williams, R. de Silva, D. Paviour, et al. (Brain-2004-01045.R1)

When J. Clifford Richardson presented the first clinical report of eight cases of progressive supranuclear palsy (PSP) at the American Neurological Association meeting in June 1963, a number of eminent discussants felt that the condition must be rare, and wondered whether a toxic aetiology might be responsible, as the cases were clustered in Ontario, Canada. With impressive foresight, Richardson remarked: ‘I doubt very much that there is any local geographic incidence. I expect that a good many cases of the same disease will be identified in other areas’ (Steele, 1992). Fast-forward 40 years, and the prevalence of PSP has been established by two community-based UK studies to be at least 5 per 100 000 (Schrag et al ., 1999; Nath et al ., 2001). The clinical picture of PSP, at least in its full-blown form, is now readily recognized by neurologists the world over (Burn and Lees, 2002). The patient has a fixed Mona Lisa stare, with a very low blink frequency, the head is retracted and speech is reduced to a distinctive slurred growl. The patient walks clumsily and unsteadily, with a marked tendency to fall backwards. Clothes are soiled with spilled food because the patient is unable to look at the plate when eating and also has dysphagia. Motor recklessness is an early feature of the condition, as are personality change and behavioural disturbance. Pathologically, PSP is characterized by the destruction …