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Background: Progressive supranuclear palsy (PSP) is characterized by early postural instability and gait dysfunction, with frequent falls. Rehabilitation is an important therapeutic approach for motor dysfunction in patients with PSP. However, no conclusions have yet been drawn regarding the beneficial effects of rehabilitation in PSP, including the optimal duration of rehabilitation and differences in treatment effects among PSP subtypes. Herein, we investigated the effects of short-term rehabilitation and separately analyzed the effects on patients with PSP-Richardson's syndrome (RS) and PSP-progressive gait freezing (PGF). Methods: The participants underwent several therapeutic exercise programs individualized for each participant, performed over 2 weeks. Analysis was performed on 25 patients with PSP-RS and eight with PSP-PGF. Results: Short-term rehabilitation improved the Berg Balance Scale score in both the PSP-RS and PSP-PGF groups, step length on the symptom-dominant side in PSP-RS, the coefficient of variation of step length on the symptom-dominant side, and the stance phase of the Symmetry Index in PSP-PGF. Conclusions: Overall, this 2-week short-term rehabilitation intervention was shown to have beneficial effects on balance in patients with PSP-RS and PSP-PGF. [ABSTRACT FROM AUTHOR]

Background: Various MRI markers—including midbrain and pons areas (Marea, Parea) and volumes (Mvol, Pvol), ratios (M/Parea, M/Pvol), and composite markers (magnetic resonance imaging Parkinsonism Indices 1,2; MRPI 1,2)—have been proposed as imaging markers of Richardson’s syndrome (RS) and multiple system atrophy–Parkinsonism (MSA-P). A systematic review/meta-analysis of relevant studies aiming to compare the diagnostic accuracy of these imaging markers is lacking. Methods: Pubmed and Scopus were searched for studies with >10 patients (RS, MSA-P or CBS) and >10 controls with data on Marea, Parea, Mvol, Pvol, M/Parea, M/Pvol, MRPI 1, and MRPI 2. Cohen’s d, as a measure of effect size, was calculated for all markers in RS, MSA-P, and CBS. Results: Twenty-five studies on RS, five studies on MSA-P, and four studies on CBS were included. Midbrain area provided the greatest effect size for differentiating RS from controls (Cohen’s d = −3.10; p < 0.001), followed by M/Parea and MRPI 1. MSA-P had decreased midbrain and pontine areas. Included studies exhibited high heterogeneity, whereas publication bias was low. Conclusions: Midbrain area is the optimal MRI marker for RS, and pons area is optimal for MSA-P. M/Parea and MRPIs produce smaller effect sizes for differentiating RS from controls.

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

Background: Various MRI markers—including midbrain and pons areas (Marea, Parea) and volumes (Mvol, Pvol), ratios (M/Parea, M/Pvol), and composite markers (magnetic resonance imaging Parkinsonism Indices 1,2; MRPI 1,2)—have been proposed as imaging markers of Richardson's syndrome (RS) and multiple system atrophy–Parkinsonism (MSA-P). A systematic review/meta-analysis of relevant studies aiming to compare the diagnostic accuracy of these imaging markers is lacking. Methods: Pubmed and Scopus were searched for studies with >10 patients (RS, MSA-P or CBS) and >10 controls with data on Marea, Parea, Mvol, Pvol, M/Parea, M/Pvol, MRPI 1, and MRPI 2. Cohen's d, as a measure of effect size, was calculated for all markers in RS, MSA-P, and CBS. Results: Twenty-five studies on RS, five studies on MSA-P, and four studies on CBS were included. Midbrain area provided the greatest effect size for differentiating RS from controls (Cohen's d = −3.10; p < 0.001), followed by M/Parea and MRPI 1. MSA-P had decreased midbrain and pontine areas. Included studies exhibited high heterogeneity, whereas publication bias was low. Conclusions: Midbrain area is the optimal MRI marker for RS, and pons area is optimal for MSA-P. M/Parea and MRPIs produce smaller effect sizes for differentiating RS from controls. [ABSTRACT FROM AUTHOR]

This article discusses a rare case of Huntington's disease (HD) presenting as progressive supranuclear palsy-Richardson's syndrome (PSP-RS) in a 79-year-old patient. HD is typically characterized by chorea, but this patient exhibited severe and rapidly progressive parkinsonism without chorea. The patient had a family history of HD, and genetic testing confirmed the presence of pathogenic HTT expansion. The article explores different hypotheses for the atypical presentation of HD and emphasizes the importance of considering genetic testing for HD in patients with atypical parkinsonism, even in the absence of chorea. [Extracted from the article]

Progressive supranuclear palsy causes diverse clinical presentations, including classical Richardsons syndrome and several variant phenotypes. Clinical trials of disease-modifying therapies have recently been completed, with more planned for the next 2 years. However, many people with progressive supranuclear palsy do not meet eligibility criteria for these clinical trials. Understanding clinical progression with different phenotypes would improve trial design and enhance the accuracy of risk-benefit and cost-benefit assessments of new treatments for progressive supranuclear palsy. We set out to determine rates of motor and cognitive progression of possible, probable and definite progressive supranuclear palsy, with different phenotypes, from a representative cohort in a regional UK healthcare service. Longitudinal clinical data from people with Richardsons syndrome and variant phenotypes were analysed using linear mixed-modelling, using both the full and modified versions of the Progressive Supranuclear Palsy Rating Scale, Mini-Mental State Examination and the revised Addenbrookes Cognitive Examination. Subgroup analyses considered patients meeting recent Phase II trial entry criteria and patients with neuropathological confirmation. Two hundred and twenty-seven patients [male = 59%, mean age (±standard deviation), 71.8 (±7.0) years] were followed for a mean 21.6 (±15.6) months. One hundred and seventy-four (77%) had Richardsons syndrome at the outset, 25 had cortical variant presentations (13%, frontal, corticobasal, speech and language variants) and 28 had subcortical variant presentations (14%, parkinsonism, postural instability and gait freezing variants). Across all participants, annual progression in Richardsons syndrome was faster than variant phenotypes on the Mini-Mental State Examination (-1.8 versus -0.9/year, P = 0.005) and revised Addenbrookes Cognitive Examination (-5.3 versus -3.0/year, P = 0.01) but not the Progressive Supranuclear Palsy Rating Scale (9.0 versus 7.1/year, P = 0.2) nor the modified Progressive Supranuclear Palsy Rating Scale (2.7 versus 2.3/year, P = 0.4). However, for those with more than 1 years follow-up, a significant difference was observed between Richardsons syndrome and variant phenotypes in Progressive Supranuclear Palsy Rating Scale (8.7 versus 6.3/year, P = 0.04). Survival was longer in variant phenotypes than Richardsons syndrome [7.3 (±3.9) versus 5.6 (±2.0) years, P = 0.02]. Pathologically confirmed cases (n = 49) supported these findings. Patients meeting basic trial-eligibility criteria (n = 129) progressed faster on the Progressive Supranuclear Palsy Rating Scale than trial-not-eligible patients (10.1 versus 6.1/year, P = 0.001). In conclusion, phenotypes other than Richardsons syndrome show slower progression and longer survival. Trial criteria do not select representative progressive supranuclear palsy cases. This has implications for trial design, and application of trial results to clinically more diverse patient populations.

Background: Progressive supranuclear palsy (PSP) is a clinically heterogenous atypical parkinsonian syndrome. Therefore, early recognition and correct diagnosis of PSP is challenging but essential. This study aims to characterize the clinical manifestations, magnetic resonance imaging (MRI), and longitudinal MRI changes of PSP in China. Method: Clinical and MRI presentations were compared among 150 cases with PSP. Then the longitudinal MRI changes among 20 patients with PSP were further explored. Additionally, a series of midbrain-based MRI parameters was compared between PSP-P and PD. Results: Throughout the course of the disease, there were differences in the symptoms of the fall and hand tremor between the PSP-RS and PSP-P. There were significant differences in the six midbrain-based MRI parameters between the PSP-RS and the PSP-P, including hummingbird sign, midbrain diameter, midbrain to pons ratio (MTPR), midbrain area, midbrain area to pons area ratio (Ma/Pa), and midbrain tegmental length (MBTegm). Longitudinal MRI studies revealed that the annual rel. MTPR and rel. (Ma/Pa) for PSP were 5.55 and 6.52%, respectively; additionally, PSP-RS presented a higher decline rate than PSP-P. Moreover, MTPR =0.56, midbrain diameter = 0.92, midbrain area = 1.00, and third ventricle width = 0.75 could identify PSP-P from PD. Conclusion: PSP-P differs from PSP-RS regarding clinical manifestations, MRI, and longitudinal MRI changes. MRI parameters could be potential imaging markers to identify PSP-P from PD. [ABSTRACT FROM AUTHOR]

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.

Background: Previous studies with a limited sample size suggested more severe dopaminergic transporter (DAT) lesions in the striatum of progressive supranuclear palsy (PSP) than those in Parkinson's disease (PD) and multiple system atrophy–parkinsonism (MSA‐P). However, few studies had taken various subtypes of PSP into consideration, making the reanalysis of DAT imaging in larger PSP cohort with various subtypes in need. Objectives: To compare the dopaminergic lesion patterns of PSP with MSA‐P and PD, and to explore the specific striatal subregional patterns of different PSP subtypes. Methods: 11C‐CFT positron emission tomography (PET) imaging was conducted in 83 PSP patients consisting of different subtypes, 61 patients with PD, 41 patients with MSA‐P, and 43 healthy volunteers. Demographic and clinical data were compared by the chi‐squared test or one‐way analysis of variance. A generalized linear model was used to examine intergroup differences in tracer uptake values after adjusting for age, disease duration, and disease severity. Areas under the receiver operating characteristic curve were calculated to assess the diagnostic accuracy of subregional DAT binding patterns. Results: The patients with PSP presented more severe DAT loss in the striatum than in PD and MSA‐P, especially in caudate. In PSP, the subregional lesion was still more severe in putamen than in caudate, similar to that in PD and MSA‐P. Among detailed subtypes, no significant difference was detected. Conclusion: The dopaminergic lesions were more severe in PSP, and no difference was detected among subtypes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To determine the usefulness of MRI measurements in patients with pure akinesia with gait freezing (PAGF), Richardson's syndrome, and Parkinson's disease for diagnosis. Methods: We obtained MRI measurements for patients with PAGF, Richardson's syndrome, or Parkinson's disease: 9 patients with PAGF, 26 with Richardson's syndrome, and 93 with Parkinson's disease. We measured the area of the pons and midbrain on midsagittal MRIs and the midbrain width on axial MRIs. We also calculated the mean values of the superior cerebellar peduncle, middle cerebellar peduncle, and cerebral crus width; the pons area-to-midbrain area ratio; the middle cerebellar peduncle width-to-superior cerebellar peduncle width ratio; and the magnetic resonance (MR) Parkinsonism index. Results: The Richardson's syndrome group had the highest pons area-to-midbrain area ratio and MR Parkinsonism index; the Parkinson's disease group had the lowest values. The Parkinson's disease group also had the highest midbrain width and cerebral crus width, with the lowest values being seen in the Richardson's syndrome group. The PAGF group had the intermediate values of the pons area-to-midbrain area ratio and MR Parkinsonism index between the Richardson's syndrome group and the Parkinson's disease group, whereas significant differences were found only in the pons area-to-midbrain area ratio. Results from receiver operating characteristic curve analyses showed that the pons area-to-midbrain area ratio has a higher sensitivity, specificity, and accuracy than the MR Parkinsonism index. Conclusions: The pons area-to-midbrain area ratio is more useful to distinguish PAGF from Richardson's syndrome and Parkinson's disease than the MR Parkinsonism index. [ABSTRACT FROM AUTHOR]

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 cm2vs. 1.29 cm2, p < 0.001, Pre-PSP-RS vs. controls = 1.01 cm2vs. 1.29 cm2, p < 0.001; P/M ratio, Pre-PSP-RS vs. PD = 5.27 vs. 4.03, p < 0.001, Pre-PSP-RS vs. controls = 5.27 cm2vs. 4.06 cm2, p < 0.001). The P/M ratio had high sensitivity (vs. PD, 96.3%, vs. control, 88.9%) and specificity (vs. PD, 81.5%, vs. control, 96.3%) in differentiating Pre-PSP-RS patients from PD and control subjects.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. [ABSTRACT FROM AUTHOR]

Sixty years ago, Steele, Richardson and Olszewski designated progressive supranuclear palsy (PSP) as a new clinicopathological entity in their seminal paper. Since then, in addition to the classic Richardson’s syndrome (RS), different clinical phenotypic presentations have been linked with this four-repeat tauopathy. The clinical heterogeneity is associated with variability of regional distribution and severity of abnormal tau accumulation and neuronal loss. In PSP subtypes, the presence of certain clinical pointers may be useful for antemortem prediction of the underlying PSP-tau pathology. Midbrain atrophy on conventional MRI correlates with the clinical phenotype of RS but is not predictive of PSP pathology. Cerebrospinal fluid biomarkers and tau ligand positron emission tomography are promising biomarkers of PSP. A multidisciplinary approach to meet the patients’ complex needs is the current core treatment strategy for this devastating disorder.

Background: Elevated uptake of the [18 F]AV-1451 tau-PET ligand has been observed cross-sectionally in subjects with progressive supranuclear palsy (PSP). However, it is unknown how the ligand performs longitudinally in PSP. We aimed to determine how regional measures of change on [18 F]AV-1451 PET perform as longitudinal biomarkers of PSP compared with the more established biomarker of rate of midbrain atrophy.Methods: Sixteen subjects with PSP underwent 2 serial [18 F]AV-1451 tau-PET scans and 3-Tesla MRI over 12 months and were age- and sex-matched to 39 healthy controls with longitudinal [18 F]AV-1451 PET. Median [18 F]AV-1451 uptake was calculated for each scan for regions of interest across the brain and divided by uptake in cerebellar crus to create standard uptake value ratios. Midbrain volume on MRI was also calculated for each scan. Sample sizes required to power placebo-controlled treatment trials were calculated.Results: Rate of midbrain atrophy was significantly increased in PSP compared with controls. [18 F]AV-1451 regional change measures were significantly increased in PSP compared with controls in the pallidum, precentral cortex, dentate nucleus of the cerebellum, and midbrain. Change over time in the PSP Rating Scale correlated with change in midbrain volume but did not correlate with change in the [18 F]AV-1451 measures. Smallest sample-size estimates were obtained with rate of midbrain atrophy, followed by the PSP Rating Scale, with both outperforming [18 F]AV-1451 measures.Conclusions: [18 F]AV-1451 tau-PET measures increase over time in subjects with PSP, but longitudinal [18 F]AV-1451 measures may not perform as well as rate of midbrain atrophy as biomarkers for PSP clinical trials. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: The differentiation of progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) remains a major clinical challenge.Objectives: To evaluate the diagnostic potential of observer-independent assessments of microstructural integrity within infratentorial brain regions to differentiate PSP-Richardson's syndrome (PSP-RS), PSP-P and PD.Methods: 3T MRI parameters of mean diffusivity, fractional anisotropy, grey and white matter volumes from patients with PSP-RS (n = 12), PSP-P (n = 12) and mean disease duration of 2.4 ± 1.7 years were compared with PD patients (n = 20) and healthy controls (n = 23) by using statistical parametric mapping and the spatially unbiased infratentorial template. Subsequently MRI measurements of the dentatorubrothalamic tract were determined observer-independently by a validated probabilistic infratentorial atlas. The impairment of gait and postural stability was evaluated by a sum-score derived from the Unified Parkinson Disease Rating Scale.Results: Significant mean diffusivity increases, fractional anisotropy decreases and corresponding volume loss were localized in mesencephalic tegmentum, superior cerebellar peduncle, decussation of superior cerebellar peduncle and dentate nucleus in PSP-RS and PSP-P compared to PD and healthy controls. Altered microstructural integrity of the dentatorubrothalamic tract in PSP-RS was significantly more pronounced compared to PSP-P and correlated significantly with the gait and postural stability sum-score. Linear discriminant analysis identified diffusion tensor imaging measures of the dentatorubrothalamic tract and the gait and postural stability sum-score to classify correctly 95.5% of PRP-RS, PSP-P and PD patients.Conclusions: Observer-independent analysis of microstructural integrity within the dentatorubrothalamic tract in combination with assessments of gait and postural stability differentiate PSP-P from PSP-RS and PD in early to moderately advanced stages. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: To elucidate different patterns of progression of mid-brain atrophy in patients with Richardson's syndrome (RS), progressive supranuclear palsy-parkinsonism (PSP-P), and Parkinson's disease (PD) using magnetic resonance imaging (MRI)-based visual rating indexes. Methods: We recruited 12 patients with PSP-RS, 12 with PSP-P, and 23 with PD for whom MRIs had been followed up for at least 2 years (mean ± SD, 4.9 ± 1.6 years) after the initial MRI. MRI-based visual rating indexes were used to estimate midbrain atrophy, including the ratio of the pontine to midbrain tegmental areas (P/M ratio) on a midsagittal image, the length between the interpeduncular fossa and the center of the cerebral aqueduct at the midmammillary-body level (MTEGM) on axial images, and the morning glory sign. Results: Initially, there were no differences in MRI-based visual rating indexes between PSP-P and PD, while PSP-RS showed a higher P/M ratio and lower MTEGM compared with PSP-P and PD. In PD, the P/M ratio and MTEGM remained stable with disease progression. However, the extent of changes between initial and follow-up indexes was similarly greater for both PSP-RS and PSP-P than for PD. Finally, PSP-P showed a higher P/M ratio and lower MTEGM compared with PD in the follow-up, while PSP-RS still exhibited the most profound changes. Conclusions: Midbrain atrophy progresses differentially in patients with PSP-RS, PSP-P, and PD. Longitudinal measurements of midbrain atrophy using MRI-based visual rating indexes can help distinguish patients with PSP-P from those with PSP-RS and PD. [ABSTRACT FROM AUTHOR]

The clinical differentiation of progressive supranuclear palsy from Parkinson's disease can be challenging, due to overlapping clinical features and a lack of diagnostic markers. Abnormalities in cognitive function form part of the clinical spectrums of these diseases and distinctive cognitive profiles may be helpful in differentiating these diseases in the diagnostic period. A comprehensive neuropsychological test battery was administered to 12 patients with clinically diagnosed progressive supranuclear palsy and 12 patients with Parkinson's disease matched for age and disease duration. Effect size ( Cohen's d) was calculated for cognitive tests that were significantly different between groups. Patients with progressive supranuclear palsy performed significantly worse than those with Parkinson's disease on measures of processing speed, verbal fluency, planning, verbal abstract reasoning, verbal memory, and made more perseverative responses on a set shifting task. Measures of executive function, manual dexterity and processing speed were most diagnostically useful ( Cohen's d > 2.0) in differentiating between progressive supranuclear palsy and Parkinson's disease. These findings suggest that more severe and prominent 'frontal' cognitive deficits in patients with progressive parkinsonism would be helpful in predicting progressive supranuclear palsy rather than Parkinson's disease and these findings may contribute to the development of diagnostic criteria. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) is a neurodegenerative disease characterized by postural instability and vertical gaze palsy, but the clinical diagnosis of PSP-RS is often difficult in the early stage of the disease. A 64-year-old male experienced frequent falls, followed by dysarthria and dysphagia. Neurological examination at age 64 demonstrated vertical gaze palsy, dysarthria, dysphagia, and retropulsion. At that time, while brain MRI demonstrated no apparent abnormalities, SPECT showed the reduction of the cerebral blood flow in the thalamus as well as the medial frontal lobe cortices. The patient was diagnosed with probable PSP-RS, and died at age 70. On postmortem examination, there were abundant tuft-shaped astrocytes, neurofibrillary tangles, coiled bodies, and argyrophilic threads in the brain, establishing the diagnosis of PSP-RS. Our definite PSP-RS case suggests that thalamic hypoperfusion may provide helpful evidence to support a diagnosis of PSP-RS in the early stage of the disease. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

In order to determine the relationship between regional neuropathology and severity of clinical features in Richardson's syndrome (PSP-RS), the following hypotheses were tested: (1) executive dysfunction relates to prefrontal pathology; (2) language difficulties to pathology in Broca's area and/or the perirhinal cortex; and (3) visuospatial impairment to pathology in the supramarginal region. A prospectively studied case series of brain donors at a specialist clinic in Addenbrooke's Hospital Cambridge, UK, were examined. All those fulfilling postmortem criteria for PSP-RS and their last cognitive assessment within 24 months of death ( N = 11/25) were included. The degree of regional neuronal loss and neuronal tau deposition across a number of cortical brain regions was performed and compared to 10 age- and sex-matched controls from the Sydney Brain Bank. Stepwise multiple linear regressions were used to determine the neuropathological correlates to cognitive scores and revealed the following . Executive dysfunction, as indexed by letter fluency, related to the degree of tau deposition in the superior frontal gyrus and supramarginal cortices ( p < 0.020), language deficits related to neuron loss in the perirhinal gyrus ( p < 0.001) and tau deposition in Broca's area ( p = 0.020), while visuospatial dysfunction and global cognitive impairment related to tau deposition in the supramarginal gyrus ( p < 0.007). The severity of cognitive deficits relate to regional cortical tau deposition in PSP-RS, although language impairment related to neuronal loss in the perirhinal region. Global cognitive dysfunction related most to the severity of tau deposition in the supramarginal gyrus warranting further research on the role of this brain region in PSP-RS. [ABSTRACT FROM AUTHOR]

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 2 years 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Vertical gaze palsy is a highly relevant clinical sign in parkinsonian syndromes. As the eponymous sign of progressive supranuclear palsy (PSP), it is one of the core features in the diagnosis of this disease. Recent studies have suggested a further differentiation of PSP in Richardson's syndrome (RS) and PSP-parkinsonism (PSPP). The aim of this study was to search for oculomotor abnormalities in the PSP-P subset of a sample of PSP patients and to compare these findings with those of (i) RS patients, (ii) patients with idiopathic Parkinson's disease (IPD), and (iii) a control group. Twelve cases of RS, 5 cases of PSP-P, and 27 cases of IPD were examined by use of video-oculography (VOG) and compared to 23 healthy normal controls. Both groups of PSP patients (RS, PSP-P) had significantly slower saccades than either IPD patients or controls, whereas no differences in saccadic eye peak velocity were found between the two PSP groups or in the comparison of IPD with controls. RS and PSP-P were also similar to each other with regard to smooth pursuit eye movements (SPEM), with both groups having significantly lower gain than controls (except for downward pursuit); however, SPEM gain exhibited no consistent difference between PSP and IPD. A correlation between eye movement data and clinical data (Hoehn & Yahr scale or disease duration) could not be observed. As PSP-P patients were still in an early stage of the disease when a differentiation from IPD is difficult on clinical grounds, the clear-cut separation between PSP-P and IPD obtained by measuring saccade velocity suggests that VOG could contribute to the early differentiation between these patient groups. [ABSTRACT FROM AUTHOR]

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. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy with neurodegeneration typically observed in the superior cerebellar peduncle (SCP) and dentatorubrothalamic tracts (DRTT). However, it is unclear how these tracts are differentially affected in different clinical variants of PSP., Objectives: To determine whether diffusion tractography of the SCP and DRTT can differentiate autopsy-confirmed PSP with Richardson's syndrome (PSP-RS) and PSP with predominant speech/language disorder (PSP-SL)., Methods: We studied 22 autopsy-confirmed PSP patients that included 12 with PSP-RS and 10 with PSP-SL. We compared these two groups to 11 patients with autopsy-confirmed Alzheimer's disease with SL problems, i.e., logopenic progressive aphasia (AD-LPA) (disease controls) and 10 healthy controls. Whole brain tractography was performed to identify the SCP and DRTT, as well as the frontal aslant tract and superior longitudinal fasciculus. We assessed fractional anisotropy and mean diffusivity for each tract. Hierarchical linear modeling was used for statistical comparisons, and correlations were assessed with clinical disease severity, ocular motor impairment, and parkinsonism. DRTT connectomics matrix analysis was also performed across groups., Results: The SCP showed decreased fractional anisotropy for PSP-RS and PSP-SL and increased mean diffusivity in PSP-RS, compared to controls and AD-LPA. Right DRTT fibers showed lower fractional anisotropy in PSP-RS and PSP-SL compared to controls and AD-LPA, with PSP-RS also showing lower values compared to PSP-SL. Reductions in connectivity were observed in infratentorial DRTT regions in PSP-RS vs cortical regions in PSP-SL. PSP-SL showed greater abnormalities in the frontal aslant tract and superior longitudinal fasciculus compared to controls, PSP-RS, and AD-LPA. Significant correlations were observed between ocular motor impairment and SCP in PSP-RS (p = 0.042), and DRTT in PSP-SL (p = 0.022). In PSP-SL, the PSP Rating Scale correlated with the SCP (p = 0.045) and DRTT (p = 0.008), and the Unified Parkinson's Disease Rating Scale correlated with the DRTT (p = 0.014)., Conclusions: Degeneration of the SCP and DRTT are diagnostic features of both PSP-RS and PSP-SL and associations with clinical metrics validate the role of these tracts in PSP-related clinical features, particularly in PSP-SL., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized pathologically by 4 repeat tau deposition in various cell types and anatomical regions. Richardson's syndrome (RS) is the initially described and one of the clinical phenotypes associated with PSP pathology, characterized by vertical supranuclear gaze paly in particular downwards, postural instability with early falls and subcortical frontal dementia. PSP can manifest as several other clinical phenotypes, including PSP-parkinsonism, -pure akinesia with gait freezing, -frontotemporal dementia, - corticobasal syndrome, - speech/language impairment. RS can also have a pathologic diagnosis other than PSP, including corticobasal degeneration, FTD-TDP-43 and others. New clinical diagnostic criteria take into account this phenotypic variability in an attempt to diagnose the disease earlier, given the current lack of a validated biomarker. At present, therapeutic options for PSP are symptomatic and insufficient. Recent large neuroprotective trials have failed to provide a positive clinical outcome, however, have led to the design of better studies that are ongoing and hold promise for a neuroprotective treatment for PSP., (Copyright © 2019 Elsevier Inc. All rights reserved.)