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Introduction The MDS-PSP criteria expand the phenotypic spectrum of PSP by adding to Richardson's syndrome (PSP-RS) other presentations such as PSP-parkinsonism (PSP–P), PSP-pure-gait-freezing (PSP-PGF), PSP-speech-language (PSP-SL), PSP-frontal (PSP–F), PSP-postural-instability (PSP-PI) and PSP-corticobasal-syndrome (PSP-CBS). Evidence about the prognostic differences between PSP phenotypes is scarce and focused on PSP-RS vs. non-PSP-RS. Using a brain-bank cohort we assessed PSP survival not only in PSP-RS vs. non-PSP-RS, but also in PSP-RS + cortical vs. subcortical phenotypes. Besides, we assessed sensitivity and specificity of the MDS-PSP criteria in of PSP and other degenerative parkinsonisms. Methods We retrospectively applied the MDS-PSP diagnostic criteria to 32 definite PSP cases and 30 cases with other degenerative parkinsonian syndromes (Parkinson's disease [PD; n = 11], multiple system atrophy [MSA; n = 11], corticobasal degeneration [CBD; n = 8]). We conducted survival statistics in neuropathologically confirmed PSP cases considering PSP-RS vs. non-PSP-RS and PSP-RS + PSP-cortical (PSP–F + PSP-SL + PSP-CBS) vs. PSP-subcortical (PSP–P + PSP-PGF) phenotypes. We also adjusted survival analyses for PSP tau scores. Results Diagnostic sensitivity was 100% and specificity ranged from 47% to 87% when excluding cases that met the “suggestive of PSP” definition early in their disease course but with other clinical features better matching with a non-PSP pathological diagnosis. Survival was significantly shorter in PSP-RS vs. non-PSP-RS cases, but it was more markedly shorter in PSP-RS + PSP-cortical vs. PSP-subcortical, independently of PSP tau scores, which were not associated with survival. Conclusions PSP-subcortical phenotypes appear to have longer survival than PSP-RS and cortical phenotypes. This might be of prognostic relevance when informing patients upon clinical diagnosis.

Introduction In the present study, midbrain atrophy and the pons-to-midbrain area ratio (P/M ratio) were investigated as diagnostic markers for presymptomatic progressive supranuclear palsy-Richardson's syndrome (Pre-PSP-RS). Methods The present study included 27 patients with probable PSP-RS who underwent brain MRI at least twice before and after the development of clinical symptoms, age- and sex-matched participants with Parkinson's disease (PD, n = 27), and healthy controls (n = 27). The midbrain area, pons area, and P/M ratio of the Pre-PSP-RS, PD, and control subjects were measured using midsagittal images from brain MRI, and the parameters were compared among the groups. Results The midbrain area decreased and the P/M ratio increased significantly in the Pre-PSP-RS patients compared with both the PD and control subjects (midbrain, Pre-PSP-RS vs. PD = 1.01 cm2 vs. 1.29 cm2, p Conclusion Midbrain atrophy precedes the clinical symptoms of PSP-RS and could be a useful diagnostic imaging biomarker for Pre-PSP-RS. Furthermore, this information could play an important role in the development of future treatment strategies.

Background Richardson’s syndrome (RS) is considered the most symmetric phenotype of progressive supranuclear palsy (PSP) as opposed to PSP with predominant corticobasal syndrome (PSP-CBS) or parkinsonism (PSP-P). Objectives Evaluate asymmetrical motor and higher cortical features in probable PSP-RS and compare the degree of asymmetry of cortical lobes and hemispheres between PSP-RS, PSP-CBS, PSP-P, and age-matched healthy controls (HC). Methods Asymmetry of motor and higher cortical features evaluated with an extensive videotaped neurologic examination was investigated in 28 PSP-RS, 8 PSP-CBS, and 14 PSP-P. Brain MRI to compute the laterality index (LI) was performed in 36 patients as well as in 56 HC. Results In PSP-RS, parkinsonism was the most common asymmetric motor feature (53.6%), followed by dystonia and myoclonus (21.4% and 17.9%, respectively). Among higher cortical features, limb apraxia was found asymmetric in about one-third of patients. PSP-RS disclosed higher LI for hemispheres compared to HC, indicating a greater degree of asymmetry (p = 0.003). The degree of asymmetry of clinical features was not different between PSP-RS and those qualifying for PSP-CBS or PSP-P. As for imaging, LI was not different between PSP-RS, PSP-CBS, and PSP-P in any cortical region. Conclusions Motor and higher cortical features are asymmetric in up to 50% of PSP-RS who also present a greater degree of asymmetry in hemispheres compared to age-matched HC. Lateralization of clinical features should be annotated in PSP.

Four-repeat tauopathies are a neurodegenerative disease characterized by brain parenchymal accumulation of a specific isoform of the protein tau, which gives rise to a wide breadth of clinical syndromes encompassing diverse symptomatology, with the most common syndromes being progressive supranuclear palsy-Richardson’s and corticobasal syndrome. Despite the lack of effective disease-modifying therapies, targeted treatment of symptoms can improve quality of life for patients with 4-repeat tauopathies. However, managing these symptoms can be a daunting task, even for those familiar with the diseases, as they span motor, sensory, cognitive, affective, autonomic, and behavioral domains. This review describes current approaches to symptomatic management of common clinical symptoms in 4-repeat tauopathies with a focus on practical patient management, including pharmacologic and nonpharmacologic strategies, and concludes with a discussion of the history and future of disease-modifying therapeutics and clinical trials in this population. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00888-5) contains supplementary material, which is available to authorized users.

A progressive speech/language disorder, such as the non fluent/agrammatic variant of primary progressive aphasia and progressive apraxia of speech, can be due to neuropathologically verified Progressive Supranuclear Palsy (PSP). The prevalence of linguistic deficits and the linguistic profile in PSP patients who present primarily with a movement disorder is unknown. In the present study, we investigated speech and language performance in a sample of clinically diagnosed PSP patients using a comprehensive language battery, including, besides traditional language tests, a detailed analysis of connected speech (picture description task assessing 26 linguistic features). The aim was to identify the most affected linguistic levels in seventeen PSP with a movement disorder presentation, compared to 21 patients with Parkinson's disease and 27 healthy controls. Machine learning methods were used to detect the most relevant language tests and linguistic features characterizing the language profile of PSP patients. Our results indicate that even non-clinically aphasic PSP patients have subtle language deficits, in particular involving the lexical-semantic and discourse levels. Patients with the Richardson's syndrome showed a lower performance in the word comprehension task with respect to the other PSP phenotypes with predominant frontal presentation, parkinsonism and progressive gait freezing. The present findings support the usefulness of a detailed language assessment in all patients in the PSP spectrum.

Tauopathies are a group of neurodegenerative diseases characterized by pathological intracellular deposits of the protein tau. Isoform composition, morphology and anatomical distribution of cellular tau-immunoreactivities are defining distinct tauopathies as molecular pathological disease entities. The clinical spectrum of tauopathies includes syndromes with primary motor symptoms and with primary cognitive dysfunction. The traditional syndrome-based classification is currently being complemented by a molecular-pathological classification. While the syndrome-based classification is helpful to select symptomatic therapies, and to generate clinical working hypotheses about underlying etiologies, the molecular-pathological classification is most important for the development and application of molecularly tailored disease-modifying therapies.

Purpose Diagnosing corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is often difficult due to the wide variety of symptoms and overlaps in the similar clinical courses and neurological findings. The purpose of this study was to evaluate the utility of white matter (WM) atrophy for the diagnosis of patients with clinically diagnosed CBD (corticobasal syndrome, CBS) and PSP (Richardson’s syndrome, RS). Methods We randomly divided the 3D T1-weighted MR images of 18 CBS patients, 33 RS patients, and 32 age-matched controls into two groups. We obtained segmented WM images in the first group using Voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) based on statistical parametric mapping (SPM) 8 plus diffeomorphic anatomical registration through exponentiated Lie algebra. A target volume of interest (VOI) for disease-specific atrophy was subsequently determined in this group using SPM8 group analyses of WM atrophy between patients groups and controls. We then evaluated the utility of these VOIs for diagnosing CBS and RS patients in the second group. Z score values in these VOIs were used as the determinant in receiver operating characteristic (ROC) analyses. Results Specific target VOIs were determined in the bilateral frontal subcortical WM for CBS and in the midbrain tegmentum for RS. In ROC analyses, the target VOIs of CBS and RS compared to those of controls exhibited an area under curve (AUC) of 0.99 and 0.84, respectively, which indicated an adequate diagnostic power. The VOI of CBS revealed a higher AUC than that of RS for differentiating between CBS and RS (AUC, 0.75 vs 0.53). Conclusions Bilateral frontal WM volume reduction demonstrated a higher power for differentiating CBS from RS. This VOI analysis is useful for clinically diagnosing CBS and RS., Highlights ・We evaluate the utility of white matter (WM) atrophy for the diagnosis of patients with corticobasal syndrome (CBS) and Richardson’s syndrome (RS). ・We obtained segmented WM images using Voxel-based specific regional analysis system for Alzheimer’ s disease based on statistical parametric mapping 8 plus diffeomorphic anatomical registration through exponentiated Lie algebra. ・The most significant areas of atrophy observed in CBS patients compared to the controls were in the bilateral frontal subcortical WM. ・The most significant areas of atrophy observed in RS patients compared to the controls were in the midbrain. ・The volume of interest analysis using bilateral frontal WM volume reduction demonstrated a higher power for differentiating CBS from RS.

Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that is sometimes confused with Parkinson's disease, multiple system atrophy, and other disorders. The typical clinical features are categorized as Richardson's syndrome (RS), but other clinical subtypes include PSP-parkinsonism (PSP-P) and PSP-pure akinesia with gait freezing (PSP-PAGF). In this study, we determined the prevalence of PSP in a Japanese rural area compared to our previous 1999 report. Methods We collected data in Yonago City from 2009 to 2014 using a service-based study of PSP. We collected case history data from PSP patients in the area from our hospital. The crude prevalence and 95% confidence interval (CI) were calculated using the population demographics on the prevalence day of 1 October 2010. Age- and sex-adjusted prevalence was calculated by direct standardization to the population demographics in Yonago City on the prevalence day of 1 April 1999. Material and Results We identified 25 patients: 16 with probable RS, 4 with possible RS, 3 with clinical PSP-P, and 2 with clinical PSP-PAGF. The prevalence per 100,000 was 17.90 (male = 18.05; female = 17.76). The prevalence of PSP in Yonago in 2010 increased compared to the measurements from 1999. Conclusion The prevalence of PSP in Japan increased from 1999 to 2010.

Progressive supranuclear palsy (PSP) is an adult onset neurodegenerative condition associated with mobility, balance, speech, swallowing, vision and cognitive changes. The condition is diagnosed using the National Institute for Neurological Disorders and Stroke (NINDS) and the Society of Progressive Supranuclear Palsy (SPSP) criteria. Therapeutic interventions for PSP are important, and a healthcare team should include a physiotherapist, occupational therapist and speech therapist. Mobility, speech and swallowing problems are commonly experienced, and aspiration pneumonia is the leading cause of death. A preliminary search of the literature has indicated that beyond small case series, there is very little evidence to guide specific allied health therapies in PSP. Many strategies for optimizing independence and function for PSP predominately rely on data extrapolated from the study of Parkinson's disease.The objective of this review was to examine the effectiveness of physical, occupational and speech therapy interventions in the symptomatic management of PSP.This review included participants with PSP as per the NINDS and the SPSP criteria, aged over 40 years of age from all community and clinical settings.This review included studies evaluating any allied health therapy that addressed mobility, vision, swallowing, communication or cognitive/neuropsychiatric difficulties experienced by patients with PSP. Studies examining interventions within the current scope of practice, and emerging interventions (non-invasive brain stimulation therapy) were eligible for inclusion.The effectiveness of interventions of interest was compared with usual care and/or baseline measurements.Outcomes of interest included the degree of change, or no change, in the symptoms experienced by patients with PSP relevant to allied health. These included difficulties with mobility, vision, swallowing, communication and cognition.All types of quantitative study designs published in English from the time of development of the NINDS and the SPSP criteria in 1996-2014 were considered for inclusion.A broad range of synonyms for PSP and a three-step search strategy was utilized to identify possible published and unpublished studies from 11 different databases. An initial limited search via MEDLINE (PubMed), CINAHL, Health Informit, PsycINFO, PEDRO, OTSeeker and SpeechBite was undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. A second search using all identified keywords and index terms was then undertaken across all included databases. Third, hand-searching was conducted and the reference list of all identified reports and articles was searched for additional studies.Critical appraisal was conducted by two independent reviewers using standardized instruments.Quantitative data were extracted from articles included in the review using standardized data extraction tools.As the quantitative articles examined different interventions, pooling of data was not appropriate. Instead, the findings were presented in narrative summary and tabular form.Following methodological appraisal, six studies were included in the review. Aside from one small quasi-randomized control study, most studies were small case series and one was a case report. Five of the six studies examined the effectiveness of a range of different physiotherapy rehabilitation programs targeting gait, balance and physical capability, with one study also targeting gaze control. The sixth study examined non-invasive brain stimulation in improving gait and midline symptoms in PSP. No studies examined the effectiveness of occupational therapy or speech therapy interventions in PSP.Research into the effectiveness of allied health therapeutic interventions for PSP symptoms is in its infancy. This review found preliminary evidence to support the use of various physiotherapy rehabilitation programs to improve balance, gait and gaze control in people affected by PSP. Further research is urgently required to identify effective interventions to manage mobility, vision, swallowing, communication and cognitive/neuropsychiatric symptoms associated with this devastating condition.

Progressive supranuclear palsy (PSP) an atypical parkinsonian with a common phenotype comprising early falls, the characteristic slowing of vertical saccades and a frontal syndrome with marked apathy (Richardson's syndrome). Currently, no effective symptomatic or neuroprotective treatment is available for PSP. Current medical have a limited role in PSP. Novel experimental treatments include davunetide or tideglusib, both inhibitors of glycogen synthase kinase-3 (GSK-3) that failed to improve the clinical outcome of PSP patients in two recent studies. Future interventions aiming at tau dysfunction and passive or active immunization are ongoing or underway.

Aims Since the first description of the classical presentation of progressive supranuclear palsy (PSP) in 1963, now known as Richardson's syndrome (PSP-RS), several distinct clinical syndromes have been associated with PSP-tau pathology. Like other neurodegenerative disorders, the severity and distribution of phosphorylated tau pathology are closely associated with the clinical heterogeneity of PSP variants. PSP with corticobasal syndrome presentation (PSP-CBS) was reported to have more tau load in the mid-frontal and inferior-parietal cortices than in PSP-RS. However, it is uncertain if differences exist in the distribution of tau pathology in other brain regions or if the overall tau load is increased in the brains of PSP-CBS. Methods We sought to compare the clinical and pathological features of PSP-CBS and PSP-RS including quantitative assessment of tau load in 15 cortical, basal ganglia and cerebellar regions. Results In addition to the similar age of onset and disease duration, we demonstrated that the overall severity of tau pathology was the same between PSP-CBS and PSP-RS. We identified that there was a shift of tau burden towards the cortical regions away from the basal ganglia; supporting the notion that PSP-CBS is a ‘cortical’ PSP variant. PSP-CBS also had less severe neuronal loss in the dorsolateral and ventrolateral subregions of the substantia nigra and more severe microglial response in the corticospinal tract than in PSP-RS; however, neuronal loss in subthalamic nucleus was equally severe in both groups. Conclusions A better understanding of the factors that influence the selective pathological vulnerability in different PSP variants will provide further insights into the neurodegenerative process underlying tauopathies.

Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian syndrome comprising two main clinical subtypes: Richardson's syndrome (RS), characterized by prominent postural instability, supranuclear vertical gaze palsy and frontal dysfunction ; and PSP-parkinsonism (PSP-P) which is characterized by an asymmetric onset, tremor and moderate initial therapeutic response to levodopa. The early clinical features of PSP-P are often difficult to discern from idiopathic Parkinson's disease (PD), and other atypical parkinsonian disorders, including multiple system atrophy (MSA) and corticobasal syndrome (CBS). In addition, rare PSP subtypes may be overlooked or misdiagnosed if there are atypical features present. The differentiation between atypical parkinsonian disorders and PD is important because the prognoses are different, and there are different responses to therapy. Structural and functional imaging, although currently of limited diagnostic value for individual use in early disease, may contribute valuable information in the differential diagnosis of PSP. A growing body of evidence shows the importance of CSF biomarkers in distinguishing between atypical parkinsonian disorders particularly early in their course when disease-modifying therapies are becoming available. However, specific diagnostic CSF biomarkers have yet to be identified. In the absence of reliable disease-specific markers, we provide an update of the recent literature on the assessment of clinical symptoms, pathology, neuroimaging and biofluid markers that might help to distinguish between these overlapping conditions early in the course of the disease.

"This study investigated the regional distribution of white matter (WM) damage in Richardson's syndrome (PSP-RS) and progressive supranuclear palsy-Parkinsonism (PSP-P) using diffusion tensor (DT) magnetic resonance imaging (MRI). The DT MRI classificatory ability in diagnosing progressive supranuclear palsy (PSP) syndromes, when used in combination with infratentorial volumetry, was also quantified. In 37 PSP (21 PSP-RS, 16 PSP-P) and 42 controls, the program Tract-Based Spatial Statistics (TBSS; www.fmrib.ox.ac.uk\/fsl\/tbss) was applied. DT MRI metrics were derived from supratentorial, thalamic, and infratentorial tracts. The magnetic resonance parkinsonism index (MRPI) was calculated. All PSP harbored diffusivity abnormalities in the corpus callosum, frontoparietal, and frontotemporo-occipital tracts. Infratentorial WM and thalamic radiations were severely affected in PSP-RS and relatively spared in PSP-P. When MRPI and DT MRI measures were combined, the discriminatory power increased for each comparison. Distinct patterns of WM alterations occur in PSP-RS and PSP-P. Adding DT MRI measures to MRPI improves the diagnostic accuracy in differentiating each PSP syndrome from healthy individuals and each other.. . "

Background: The clinical and pathological heterogeneity of progressive supranuclear palsy (PSP) is well established. Recent clinicopathological studies showed much more severe and more widespread tau pathology in Richardson’s syndrome (RS), clinically manifest by early onset, falls, supranuclear gaze palsy, dementia and shorter disease duration than in atypical PSP-parkinsonism (PSP-P) often mimicking Parkinson’s disease, in which tau pathology is relatively restricted to substantia nigra, subthalamic nucleus and internal globus pallidus. Objective: To perform a comparative clinicopathological study of 30 autopsy-proven cases of PSP. Methods: Retrospective assessment of major clinical signs in 18 patients referred to as RS and 12 PSP-P, and semiquantitative assessment of the severity and distribution pattern of tau pathology in both phenotypes using routine stains and immunohistochemistry. Results: RS (61% males) and PSP-P (33% males) showed significant differences in clinical symptomatology and course (RS mean duration 4.2 years, PSP-P 13.8 years) and significant differences in histopathology: widespread tau pathology and related multisystem degeneration in RS and more restricted lesions in PSP-P, which, however, were not only involving predominantly the subthalamo-nigral-pallidal system. Cortical tau pathology in both groups was usually restricted to limbic areas, and neocortical Alzheimer-type pathology was only seen in very old or demented PSP patients. Conclusions: The present study confirmed the recently reported existence of two distinct clinical phenotypes in patients with pathologically proven PSP-P and RS, showing significant differences in severity and distribution of tau pathology, the latter more severe and more widely distributed than in PSP-P.

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 …