PSP-Richardson's Syndrome Research Articles

Impaired long-term potentiation-like motor cortical plasticity in progressive supranuclear palsy

ObjectiveTo elucidate long-term potentiation (LTP)-like effects on the primary motor cortical (M1) in progressive supranuclear palsy (PSP) and its relationships with clinical features. MethodsParticipants were 18 probable/possible PSP Richardson syndrome (PSP-RS) patients and 17 healthy controls (HC). We used quadripulse stimulation (QPS) over the M1 with an interstimulus interval of 5 ms (QPS-5) to induce LTP-like effect and analyzed the correlations between the degree of LTP-like effect and clinical features. We also evaluated cortical excitability using short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF) in 15 PSP patients and 17 HC. ResultsLTP-like effect after QPS in PSP was smaller than HC and negatively correlated with Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) score, especially bradykinesia, but not with either age or any scores of cognitive functions. The SICI was abnormally reduced in PSP, but neither ICF nor SICF differed from those of normal subjects. None of these cortical excitability parameters correlated with any clinical features. ConclusionsLTP induction was impaired in PSP. The degree of LTP could reflect the severity of bradykinesia. The bradykinesia may partly relate with the motor cortical dysfunction. SignificanceThe degree of motor cortical LTP could relate with the severity of motor symptoms in PSP.

Differentiating between common PSP phenotypes using structural MRI: a machine learning study.

Differentiating Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) from PSP-Parkinsonism (PSP-P) may be extremely challenging. In this study, we aimed to distinguish these two PSP phenotypes using MRI structural data. Sixty-two PSP-RS, 40 PSP-P patients and 33 control subjects were enrolled. All patients underwent brain 3T-MRI; cortical thickness and cortical/subcortical volumes were extracted using Freesurfer on T1-weighted images. We calculated the automated MR Parkinsonism Index (MRPI) and its second version including also the third ventricle width (MRPI 2.0) and tested their classification performance. We also employed a Machine learning (ML) classification approach using two decision tree-based algorithms (eXtreme Gradient Boosting [XGBoost] and Random Forest) with different combinations of structural MRI data in differentiating between PSP phenotypes. MRPI and MRPI 2.0 had AUC of0.88 and 0.81, respectively, in differentiating PSP-RS from PSP-P. ML models demonstrated that the combination of MRPI and volumetric/thickness data was more powerful than each feature alone. The two ML algorithms showed comparable results, and the best ML model in differentiating between PSP phenotypes used XGBoost with a combination of MRPI, cortical thickness and subcortical volumes (AUC 0.93 ± 0.04). Similar performance (AUC 0.93 ± 0.06) was also obtained in a sub-cohort of 59 early PSP patients. The combined use of MRPI and volumetric/thickness data was more accurate than each MRI feature alone in differentiating between PSP-RS and PSP-P. Our study supports the use of structural MRI to improve the early differential diagnosis between common PSP phenotypes, which may be relevant for prognostic implications and patient inclusion in clinical trials.

Characterizing gait and exploring neuro-morphometry in patients with PSP-Richardson's syndrome and vascular parkinsonism

Gait differentiation in progressive supranuclear palsy (PSP) and vascular parkinsonism (VaP) is sometimes difficult to detect with the naked eye. Here, we compared specific gait parameters, neuro-morphometric indices, and their associations between patients with PSP Richardson's syndrome (PSP-RS) and VaP. A total of 18 PSP-RS and 13 VaP patients were recruited. Spatio-temporal gait parameters (GAITRite®) and neuroanatomical morphometry (FreeSurfer pipeline) were assessed. The groups were compared using unpaired t-tests involving 10000 random permutations after statistically controlling for total UPDRS-III and H&Y scores. Statistically significant differences between the groups were decided at < 5% Benjamini-Hochberg False Discovery Rate (FDR) for multiple-comparison related corrections. Spearman's correlations were performed to assess the significant associations (p < 0.05) between the gait parameters and morphometry indices. Among all the spatio-temporal gait parameters, PSP-RS patients displayed greater stride time, step time, swing time, and stance time variabilities compared to VaP. Morphometric analyses showed that thalamus, and caudate volumes were significantly lower, but cerebellar cortex, hippocampus, amygdala, accumbens, and putamen volumes were higher in PSP-RS than VaP. Moreover, the bilateral insula was significantly thinner in VaP than in PSP-RS. Correlation analyses support the involvement of limbic structures besides cerebellum in postural control during self-paced walking of PSP-RS patients. Our findings underline the importance of examining individual brain regions to understand the association of cortical and subcortical morphometric estimates and gait variability parameters in PSP-RS and VaP. This study suggests the involvement of the limbic system in addition to the classical neural structures for motor control and gait.

Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) has been reported as a disorder mainly characterized by a tendency to fall, vertical supranuclear gaze palsy, and constriction of the body axis, akinesia, and cognitive impairment. Patients presenting with these typical clinical features are diagnosed as having the PSP-Richardson syndrome (PSP-RS). Electronystagmography (ENG) is useful for the detection of ocular motility disorder, which is the main feature of PSP. In cases of PSP, ocular motility disorder in the vertical direction occurs from the initial stage of the disease, and is characterized by prolonged latency and reduced velocity of the saccadic eye movement in the vertical direction. Horizontal saccadic eye movement disorder also occurs after the intermediate stage. Square wave jerks (SWJ) are often recognized from the initial stage of the disease. In terms of nystagmus, the quick phase is impaired due to impaired saccadic eye movements, and impairment of optokinetic nystagmus also starts from the quick phase movements. Pursuit (smooth) eye movement may also be impaired as the disease progresses. On the other hand, the vestibulo-ocular reflex is maintained even after disease progression to a late stage.

Correlation of 18F-PM-PBB3 (18F-florzolotau) Tau PET Imaging with Postmortem Neuropathological Findings in A Case with Progressive Supranuclear Palsy (P9-11.015)

<h3>Objective:</h3> To examine correlations between <i>in vivo</i> positron emission tomography (PET) imaging with 18F-PM-PBB3 (18F-florzolotau) and postmortem neuropathological findings in a patient with progressive supranuclear palsy (PSP). <h3>Background:</h3> There have been no reports demonstrating tight PET-pathology associations in the same individual with non-Alzheimer-type neurodegenerative disorders, including PSP, characterized by aggregations of four-repeat tau isoforms only. 18F-florzolotau is a PET probe allowing high-contrast imaging of Alzheimer’s and non-Alzheimer tau pathologies irrespective of isoform compositions, while the utility of this tracer for quantifying the abundance of tau deposits in living cases is yet to be verified. <h3>Design/Methods:</h3> <h3>Patient:</h3> A 65-year-old male with a clinical diagnosis of PSP Richardson syndrome underwent 11C-PiB amyloid and 18F-florzolotau tau PET scans one year before autopsy. Clinical, neuroimaging, and neuropathological findings in this case were briefly summarized elsewhere (K Tagai, et al. Neuron 2021). <h3>Image analysis:</h3> The standardized uptake value ratio (SUVR) image was generated from averaged PET images at 90–110 min after injecting 18F-florzolotau. The reference region was determined using an optimized reference tissue method (K Tagai, et al. medRxiv DOI: https://doi.org/10.1101/2022.02.13.22270135). <h3>Neuropathological analysis:</h3> Quantitative analysis of tau burden was performed using an anti-phosphorylated tau antibody (AT8). A threshold-based binarization method was used for determining the mean AT-8-positive area (%area tau burden). <h3>Results:</h3> 18F-florzolotau PET showed enhanced radiosignals in the brainstem, subthalamic nucleus, and basal ganglia, and the presence of PSP-characteristic tau deposits, including the globose neurofibrillary tangle, tufted astrocytes and coiled bodies, primarily in these areas was confirmed by neuropathological assays. There was a close correlation between regional radioprobe SUVR and %area tau burden (<i>r</i><i>_s</i> = 0.63, <i>p</i> &lt;0.0001). Amyloid PET was negative by visual read. <h3>Conclusions:</h3> 18F-florzolotau PET measures reflect the abundance of tau pathologies in PSP. <b>Disclosure:</b> Dr. Endo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for APRINOIA Therapeutics. Dr. Endo has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for AbbVie Inc.. The institution of Dr. Endo has received research support from JSPS KAKENHI 21K15705. Dr. Araki has nothing to disclose. Dr. Takeda has nothing to disclose. Dr. Takado has nothing to disclose. Dr. Tagai has nothing to disclose. Dr. Matsuoka has nothing to disclose. Dr. Seki has nothing to disclose. Dr. Takahata has nothing to disclose. Dr. Sahara has nothing to disclose. Hitoshi Shinotoh has nothing to disclose. Mr. Kawamura has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Honda has nothing to disclose. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for eli lilly. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda Pharmaceutical . Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eisai. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Nihon Medi-Physics. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for FUJIFILM Toyama Chemical. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sunplanet . Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for NIPPON CHEMIPHAR. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sumitomo Pharma. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GE Healthcare. Prof. SHIMADA has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for CHUGAI PHARMACEUTICAL. Prof. SHIMADA has received intellectual property interests from a discovery or technology relating to health care. Prof. SHIMADA has received publishing royalties from a publication relating to health care. Prof. SHIMADA has received publishing royalties from a publication relating to health care. Prof. SHIMADA has received publishing royalties from a publication relating to health care. The institution of Dr. Higuchi has received research support from APRINOIA Therapeutics.

Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome

Plasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology. To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS. This multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort. Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling. Of 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005). In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

Efficacy of faecal microbiota transplantation in patients with progressive supranuclear palsy-Richardson's syndrome: a phase 2, single centre, randomised clinical trial

Faecal microbiota transplantation (FMT) has demonstrated efficacy in treating gastrointestinal (GI) diseases, such as Clostridium difficile infection (CDI) and inflammatory bowel disease (IBD). GI dysfunction is a frequent and occasionally dominating symptom of progressive supranuclear palsy-Richardson's syndrome (PSP-RS). However, it is not known whether FMT has clinical efficacy for PSP-RS. This 36-week, randomised, placebo-controlled, parallel-group, phase 2 clinical trial was performed at a university tertiary referral hospital in China. From August 15 2021 to December 31 2021, a total of 68 newly diagnosed patients with PSP-RS (male 40 [59%], female 28 [41%]) who had never received any antiparkinsonian medications were enrolled and randomly assigned to receive either healthy donor FMT (n=34, FMT group) or a mixture of 0.9% saline and food colouring (E150c) as sham transplantation (n=34, placebo group) through transendoscopic enteral tubing (TET). Two days after oral antibiotics, participants received 1 week of transplantation. After an interval of 4 weeks, retransplantation was performed. Then, the last transplantation was given after another interval of 4 weeks, and the participants were followed up for 24 weeks (week 36). Clinicaltrials.gov identifier: ChiCTR-2100045397. Among 68 patients who were randomised (mean age, 67.2 (SD 5.1); 40 [59%] were male, 28 [41%] were female), 63 participants completed the trial. Efficacy analyses were performed on the intention-to-treat (ITT) analysis set. At week 16, the mean PSP Rating Scale (PSPRS) scores (the primary outcome) improved from 40.1 (SD 7.6) to 36.9 (SD 5.9) in the FMT group, whereas the scores changed from 40.1 (SD 6.9) to 41.7 (SD 6.2) in the placebo group, for a treatment benefit of 4.3 (95% CI, 3.2-5.4) (P<0.0001). After 3-cycle intervention, symptoms of constipation, depression, and anxiety (the secondary outcome) improved significantly at week 16 in the FMT group compared with the placebo group, the majority of which were maintained at the 24-week follow-up (week 36). Our findings suggest that, compared with placebo, FMT treatment significantly improved motor and nonmotor symptoms in patients with PSP-RS, as well as reduced intestinal inflammation and enhanced the intestinal barrier by regulating the intestinal microbiota composition. The National Natural Science Foundation of China (No. 82122022, 82171248, 81873791, and 82230084), Natural Science Foundation of Henan Province for Excellent Young Scholars (no. 202300410357), and Henan Province Young and Middle-Aged Health Science and Technology Innovation Talent Project (YXKC2020033).

18 F-Florzolotau Positron Emission Tomography Imaging of Tau Pathology in the Living Brains of Patients with Corticobasal Syndrome.

Recent development in tau-sensitive tracers has sparkled significant interest in tracking tauopathies using positron emission tomography (PET) biomarkers. However, the ability of 18 F-florzolotau PET imaging to topographically characterize tau pathology in corticobasal syndrome (CBS) remains unclear. Further, the question as to whether disease-level differences exist with other neurodegenerative tauopathies is still unanswered. To analyze the topographical patterns of tau pathology in the living brains of patients with CBS using 18 F-florzolotau PET imaging and to examine whether differences with other tauopathies exist. 18 F-florzolotau PET imaging was performed in 20 consecutive patients with CBS, 20 cognitively healthy controls (HCs), 20 patients with Alzheimer's disease (AD), and 16 patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). Cerebrospinal fluid (CSF) levels of β-amyloid biomarkers were quantified in all patients with CBS. 18 F-florzolotau uptake was quantitatively assessed using standardized uptake value ratios. Of the 20 patients with CBS, 19 (95%) were negative for CSF biomarkers of amyloid pathology; of them, three had negative 18 F-florzolotau PET findings. Compared with HCs, patients with CBS showed increased 18 F-florzolotau signals in both cortical and subcortical regions. In addition, patients with CBS were characterized by higher tracer retentions in subcortical regions compared with those with AD and showed a trend toward higher signals in cortical areas compared with PSP-RS. An asymmetric pattern of 18 F-florzolotau uptake was associated with an asymmetry of motor severity in patients with CBS. In vivo 18 F-florzolotau PET imaging holds promise for distinguishing CBS in the spectrum of neurodegenerative tauopathies. © 2023 International Parkinson and Movement Disorder Society.

PDQ-8: A Simplified and Effective Tool Measuring Life Quality in Progressive Supranuclear Palsy.

The self-reported quality of life (QoL) should be carefully listened to in progressive supranuclear palsy (PSP) from the patient-centered perspective. However, there was still a lack of short QoL measurement tool in atypical parkinsonism. We aimed to test whether the short Parkinson's Disease Questionnaire-8 (PDQ-8) was effective in assessing QoL in PSP, comparing with Progressive Supranuclear Palsy Quality of Life Scale (PSP-QoL) and Parkinson's Disease Questionnaire-39 (PDQ-39). 132 patients with clinical diagnosed PSP, including PSP-Richardson syndrome (RS) subtype (n = 71) and PSP-non-RS subtype (n = 61) were recruited for clinical evaluation including QoL assessment. The detailed QoL profiles and possibility of using PDQ-8 were systemically analyzed. The determinants to the QoL were then calculated by multivariate linear regression analysis. The PSP-QoL total score summary index (SI) was 22.8 (10.1, 41.1), while the PDQ-8 and PDQ-39 total SI score were 28.1 (12.5, 46.9) and 29.5 (15.4, 49.4). Mobility, activities of daily life, cognition and communication were the main affected QoL subdomains (median SI: 40.0, 31.3, 25.0 and 25.0 respectively). PSP-RS subtype showed more severe damage physically (p<0.001) and mentally (p = 0.002) compared to other subtypes. More importantly, the strong relevance of PDQ-8 and recommended PSP QoL tools were confirmed (p<0.001). In addition, disease severity, depression and daytime sleepiness were proved to be critical determinants for QoL in PSP. PDQ-8 could be an easy, reliable, and valid tool to evaluate QoL in patients with PSP. Besides motor symptoms, more attention should be paid to non-motor impairment such as depression in PSP.

Using Downgaze Palsy Progression Rate to Model Survival in Progressive Supranuclear Palsy-Richardson Syndrome.

Rapid development of downgaze palsy, the most specific symptom of progressive supranuclear palsy (PSP), has been associated with shorter survival in small studies. We hypothesized that the progression rate of downgaze palsy and other disease features could predict survival if assessed soon after the onset of downgaze palsy in a large data set. We used a longitudinal database of 414 patients with probable PSP-Richardson syndrome from 1994 to 2020. The data set comprised demographics and, for each visit, 28 PSP Rating Scale (PSPRS) items and PSP stage scores. We calculated the rate of progression of each PSPRS item as its item score when the downgaze item first reached 1 or more (on a 0-4 scale) divided by disease duration at that point. Multivariate Cox regression was applied to identify variables independently associated with survival. We also explored the progression pattern of total PSPRS and downgaze palsy scores with disease course. Independently associated with shorter survival were older onset age and faster progression of downgaze palsy, dysphagia for liquids, difficulty in returning to seat, and PSP stage. Patients with survival duration within 1 year of the median survival (6.58 years) showed approximately linear progression of the PSPRS score and downgaze palsy score during years 2 through 6 of the disease course. Older onset age and faster progression of downgaze palsy and several axial features are associated with shorter survival. The disease typically progresses in approximately linear fashion during years 2 through 6. These results may aid study design and patient counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Rhythmic auditory cueing in atypical parkinsonism: A pilot study.

Rhythmic auditory cueing (RAC) can improve gait parameters in neurological disorders such as Parkinson's disease and stroke. However, there is a lack of research on the effects of RAC in patients with atypical parkinsonian disorders (APD). Using a smartphone metronome application, we aimed to investigate the immediate effects of RAC in patients with clinically diagnosed APD, namely Progressive Supranuclear Palsy (PSP-Richardson Syndrome and other variants, PSP-nonRS), Corticobasal Syndrome (CBS), Multiple System Atrophy (MSA), and Dementia with Lewy Bodies (DLB). A total of 46 APD participants (25 PSP, 9 CBS, 8 MSA and 4 DLB; age: mean = 70.17, standard deviation = 7.15) walked at their preferred pace for 2 min without any rhythmic auditory cueing (RAC). Participants then walked the same path for another 2 min with RAC set at a tempo 10% faster than the baseline cadence of each participant. After a 10-15-min break, participants walked the same path for another 2 min without RAC to observe for carryover effects. Gait parameters [cadence (steps/minute), gait velocity (meters/minute), and stride length (centimeters)] were collected at baseline, during RAC, and post-RAC. There was a significant improvement in cadence in all participants from baseline to during RAC and post-RAC (corrected p-values = 0.009 for both). Gait velocity also improved from baseline to during RAC and post-RAC in all participants, although this improvement was not significant after correcting for multiple comparisons. The changes in cadence and gait velocity were most pronounced in PSP. In addition, our exploratory analysis showed that the cadence in the suspected TAU group (PSP+CBS) showed a significant improvement from baseline to during RAC and post-RAC (corr. p-value = 0.004 for both). This pilot study using short-term RAC in APD patients demonstrated improvements in cadence and velocity. There is an urgent need for effective gait rehabilitation modalities for patients with APD, and rhythmic cueing can be a practical and useful intervention to improve their gait pattern.

A Machine Learning-Based Approach to Discrimination of Tauopathies Using [18 F]PM-PBB3 PET Images.

We recently developed a positron emission tomography (PET) probe, [18 F]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed. We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities. Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others. The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively. These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Significance of Asymmetry in the Assessment of Brain Perfusion in Atypical Tauopathic Parkinsonian Syndromes.

Progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) are clinical manifestations of tauopathic Parkinsonian syndromes. Due to their overlapping symptomatology, the differential diagnosis of these entities may be difficult when bounded to clinical assessment. The manifestations are commonly associated with pathological entities—corticobasal degeneration and progressive supranuclear palsy, which are four-repeat tauopathies. In this study, the authors attempted to find whether the asymmetry typically associated with CBS may be feasible in the interpretation of perfusion single-photon computed tomography. The analysis based on the examination of patients with progressive supranuclear palsy—Richardson syndrome (PSP-RS), progressive supranuclear palsy—Parkinsonism predominant (PSP-P), and corticobasal syndrome (CBS) revealed significant asymmetry of perfusion of the amygdala in corticobasal syndrome. The more pronounced abnormalities of perfusion were observed in the left amygdala among patients with more severe Parkinsonian syndromes in CBS on the right. This study shows that the comparison of the perfusion of tauopathic Parkinsonian syndromes should be extended by asymmetry analysis. Interestingly, the differentiating potential of brain perfusion is present in the comparison of CBS and PSP-RS, but not in CBS and PSP-P. This phenomenon could be explained by more distinct asymmetry in the perfusion observed in PSP-P, which diminishes the differentiating potential of this parameter when it comes to the comparison of PSP-P and CBS. To the best of our knowledge, this is the first study evaluating which structures can be interpreted as significantly asymmetrical in the context of perfusion in CBS.

The Burden of Progressive Supranuclear Palsy on Patients, Caregivers, and Healthcare Systems by PSP Phenotype: A Cross-Sectional Study.

Progressive supranuclear palsy (PSP) is a rare, relentlessly progressive, ultimately fatal neurodegenerative brain disease. The objective of this study was to assess the burden of PSP on patients, caregivers, and healthcare systems by PSP phenotype. Data were drawn from the Adelphi PSP Disease Specific Programme™, a cross-sectional study of neurologists and people living with PSP in the United States of America, France, Germany, Italy, Spain, and the United Kingdom. All people living with PSP with a reported phenotype were included. PSP phenotype was reported for 242 patients (mean age: 70.2 years, 58% male): PSP-Richardson's syndrome, n = 96; PSP-predominant Parkinsonism, n = 88; PSP-predominant corticobasal syndrome, n = 28; PSP-predominant speech/language disorder, n = 12; PSP-progressive gait freezing, n = 9; PSP-predominant frontal presentation, n = 9. Most patients reported impaired cognitive, motor, behavioral and ocular functionality; 67–100% of patients (across phenotypes) had moderate-to-severe disease at the time of data collection. Post-diagnosis, the majority were provided with a visual and/or mobility aid (55–100%, across phenotypes), and/or required home modification to facilitate their needs (55–78%, across phenotypes). Patients required multiple types of healthcare professionals for disease management (mean 3.6–4.4, across phenotypes), and the majority reported receiving care from at least one caregiver (mean 1.3–1.8, across phenotypes). There is a high burden on patients, caregivers, and healthcare systems across all PSP phenotypes. Although phenotypes manifest different symptoms and are associated with different diagnostic pathways, once diagnosed with PSP, patients typically receive similar care.

Structural and Functional Thalamic Changes in Progressive Supranuclear Palsy

AimsStudies of thalamic structure and function in Progressive Supranuclear Palsy (PSP) suggest it may play a role in key aspects of the clinical syndrome. This study examined thalamic changes across PSP phenotypes investigating (i) thalamic atrophy (ii) thalamic functional connectivity and (iii) the relationship between thalamic structural and functional connectivity changes with clinical severity.MethodsParticipants92 participants with PSP [63 PSP-Richardson's Syndrome (RS), 24 PSP-cortical, 5 PSP-subcortical] and 104 age-matched controls were recruited from the Cambridge Centre for Parkinson's Plus Disorders cohort. Clinical assessments and imaging were conducted within 1 year of diagnosis.Structural AnalysisThalamic volumes (TVs) were obtained using FreeSurfer. Bayesian multiple regression (brms, R) was used to model (i) mean TVs (ii) group differences in mean TVs (iii) relationships between Z-standardised clinical scores and TVs with age, gender, and total grey matter as covariates.Functional AnalysisVoxel-wise seed-based functional connectivity of the thalamus used the Functional Magnetic Resonance Imaging Expert Analysis Tool (FEAT) in FMRIB's Software Library (FSL). Inter-group differences and relationships between clinical scores and functional connectivity for each group were assessed using a general linear model with age and gender as covariates.ResultsStructural AnalysisTVs for all PSP subgroups were smaller than controls. No differences between PSP subgroups were detected. There was evidence for a relationship between TVs for the entire PSP group and Revised Addenbrooke's Cognitive Examination (ACER) scores [ß = 0.28, 95% credible interval (CI) = 0.04–0.53]. Subgroup analysis showed evidence for a relationship between ACER scores and TVs in PSP-RS [ß = 0.33, 95% CI = 0.09–0.57] and PSP-cortical [ß = 0.46, 95% CI = 0.12–0.83] phenotypes. A negative influence of TVs on total PSP rating scale scores was found for the PSP cohort a whole [ß = −0.51, 95% CI = −1.00 – −0.02].Functional AnalysisPSP patients as a group showed decreased thalamic functional connectivity in higher cortical regions. Subgroup analysis revealed decreased connectivity in those areas compared to controls but in distinct distributions and magnitude. Increased thalamic connectivity with the middle temporal gyrus correlated with ACER scores for PSP patients as a group and in the PSP-cortical subtype.ConclusionThalamic volume loss is a prominent aspect of PSP and is associated with a wide network of changes in functional connectivity that may be distinct between PSP subtypes. Changes in thalamic structure and function predict clinical severity, particularly in PSP-RS and PSP-cortical subtypes.

Diagnostic Accuracy of Magnetic Resonance Imaging Measures of Brain Atrophy Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Degeneration

The accurate diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is hampered by imperfect clinical-pathological correlations. To assess and compare the diagnostic value of the magnetic resonance parkinsonism index (MRPI) and other magnetic resonance imaging-based measures of cerebral atrophy to differentiate between PSP, CBD, and other neurodegenerative diseases. This prospective diagnostic study included participants with 4-repeat tauopathies (4RT), PSP, CBD, other neurodegenerative diseases and available MRI who appeared in the University of California, San Francisco, Memory and Aging Center database. Data were collected from October 27, 1994, to September 29, 2019. Data were analyzed from March 1 to September 14, 2021. The main outcome of this study was the neuropathological diagnosis of PSP or CBD. The clinical diagnosis at the time of the MRI acquisition was noted. The imaging measures included the MRPI, cortical thickness, subcortical volumes, including the midbrain, pons, and superior cerebellar peduncle volumes. Multinomial logistic regression models (MLRM) combining different cortical and subcortical regions were defined to discriminate between PSP, CBD, and other pathologies. The areas under the receiver operating characteristic curves (AUROC) and cutoffs were calculated to differentiate between PSP, CBD, and other diseases. Of the 326 included participants, 176 (54%) were male, and the mean (SD) age at MRI was 64.1 (8.0) years. The MRPI showed good diagnostic accuracy for the differentiation between PSP and all other pathologies (accuracy, 87%; AUROC, 0.90; 95% CI, 0.86-0.95) and between 4RT and other pathologies (accuracy, 80%; AUROC, 0.82; 95% CI, 0.76-0.87), but did not allow the discrimination of participants with CBD. Its diagnostic accuracy was lower in the subgroup of patients without the canonical PSP-Richardson syndrome (PSP-RS) or probable corticobasal syndrome (CBS) at MRI. MLRM combining cortical and subcortical measurements showed the highest accuracy for the differentiation between PSP and other pathologies (accuracy, 95%; AUROC, 0.98; 95% CI, 0.97-0.99), CBD and other pathologies (accuracy, 83%; AUROC, 0.86; 95% CI, 0.81-0.91), 4RT and other pathologies (accuracy, 89%; AUROC, 0.94; 95% CI, 0.92-0.97), and PSP and CBD (accuracy, 91%; AUROC, 0.95; 95% CI, 0.91-0.99), even in participants without PSP-RS or CBS at MRI. In this study, the combination of widely available cortical and subcortical measures of atrophy on MRI discriminated between PSP, CBD, and other pathologies and could be used to support the diagnosis of 4RT in clinical practice.

A data-driven model of brain volume changes in progressive supranuclear palsy.

The most common clinical phenotype of progressive supranuclear palsy is Richardson syndrome, characterized by levodopa unresponsive symmetric parkinsonism, with a vertical supranuclear gaze palsy, early falls and cognitive impairment. There is currently no detailed understanding of the full sequence of disease pathophysiology in progressive supranuclear palsy. Determining the sequence of brain atrophy in progressive supranuclear palsy could provide important insights into the mechanisms of disease progression, as well as guide patient stratification and monitoring for clinical trials. We used a probabilistic event-based model applied to cross-sectional structural MRI scans in a large international cohort, to determine the sequence of brain atrophy in clinically diagnosed progressive supranuclear palsy Richardson syndrome. A total of 341 people with Richardson syndrome (of whom 255 had 12-month follow-up imaging) and 260 controls were included in the study. We used a combination of 12-month follow-up MRI scans, and a validated clinical rating score (progressive supranuclear palsy rating scale) to demonstrate the longitudinal consistency and utility of the event-based model’s staging system. The event-based model estimated that the earliest atrophy occurs in the brainstem and subcortical regions followed by progression caudally into the superior cerebellar peduncle and deep cerebellar nuclei, and rostrally to the cortex. The sequence of cortical atrophy progresses in an anterior to posterior direction, beginning in the insula and then the frontal lobe before spreading to the temporal, parietal and finally the occipital lobe. This in vivo ordering accords with the post-mortem neuropathological staging of progressive supranuclear palsy and was robust under cross-validation. Using longitudinal information from 12-month follow-up scans, we demonstrate that subjects consistently move to later stages over this time interval, supporting the validity of the model. In addition, both clinical severity (progressive supranuclear palsy rating scale) and disease duration were significantly correlated with the predicted subject event-based model stage (P < 0.01). Our results provide new insights into the sequence of atrophy progression in progressive supranuclear palsy and offer potential utility to stratify people with this disease on entry into clinical trials based on disease stage, as well as track disease progression.

Differential diagnosis between Parkinson's disease and atypical parkinsonism based on gait and postural instability: Artificial intelligence using an enhanced weight voting ensemble model

BackgroundParkinsonian diseases and cerebellar ataxia among movement disorders, are representative diseases which present with distinct pathological gaits. We proposed a machine learning system that can differentiate Parkinson's disease (PD), cerebellar ataxia and progressive supranuclear palsy Richardson syndrome (PSP-RS) based on postural instability and gait analysis. MethodsWe screened 1467 gait (GAITRite) and postural instability (Pedoscan) analyses performed in Samsung Medical Center from January 2019 to December 2020. PD, probable PSP-RS, and cerebellar ataxia (i.e., probable MSA-C, hereditary ataxia, and sporadic adult-onset ataxia) were included in the study. The gated recurrent units for GaitRite and the deep neural network for Pedoscan were applied. The enhanced weight voting ensemble (EWVE) method was applied to incorporate the two modalities. ResultsWe included 551 PD, 38 PSP-RS, 113 cerebellar ataxia and among them, 71 were MSA-C. Pedoscan-based and Gait-based model showed high sensitivity but low specificity in differentiating atypical parkinsonism from PD. The EWVE showed significantly improved specificity and reliable performance in differentiation between PD vs. ataxia patients (AUC 0.974 ± 0.036, sensitivity 0.829 ± 0.217, specificity 0.969 ± 0.038), PD vs. MSA-C (AUC 0.975 ± 0.020, sensitivity 0.823 ± 0.162, specificity 0.932 ± 0.030) and PD vs. PSP-RS (AUC 0.963 ± 0.028, sensitivity 0.555 ± 0.157, specificity 0.936 ± 0.031). ConclusionWe proposed reliable Pedoscan-based, Gait-based and EWVE model in differentiating gait disorders by integrating information from gait and postural instability. This model can provide diagnosis guidelines to primary caregivers and assist in differential diagnosis of PD from atypical parkinsonism for neurologists.

Pathologically Verified Corticobasal Degeneration Mimicking Richardson's Syndrome Coexisting with Clinically and Radiologically Shunt-Responsive Normal Pressure Hydrocephalus.

ABSTRACTBackgroundNormal pressure hydrocephalus (NPH) manifests as gait instability, cognitive impairment, and urinary incontinence. This clinical triad of NPH sometimes occurs with ventriculomegaly in patients with neurodegenerative disease. Patients with pathologically verified neurodegenerative diseases, such as progressive supranuclear palsy (PSP), have received antemortem diagnoses of NPH.ObjectivesThis study presents clinical and pathological features of a patient with pathologically verified corticobasal degeneration (CBD) coexisting with clinically shunt‐responsive NPH.MethodsWe performed clinical, radiological, and pathological evaluations in a patient with CBD whose antemortem diagnosis was PSP Richardson's syndrome (PSP‐RS) coexisting with shunt‐responsive NPH.ResultsA 59‐year‐old woman developed bradykinesia and gait instability and then frequent falls, urinary incontinence, and supranuclear vertical gaze palsy followed. At 63 years of age, her gait disturbance and urinary incontinence had deteriorated rapidly, and cognitive impairment was disclosed. There were typical findings of NPH with ventriculomegaly and disproportionately enlarged subarachnoid space hydrocephalus as well as a 2‐layer appearance with decreased and increased cerebral blood perfusion. Shunt placement ameliorated gait instability for more than 1 year and improved radiological indicators of NPH. However, atrophy of the midbrain progressed with time after transient increases in size. Although the antemortem diagnosis was probable PSP‐RS, pathological evaluation verified CBD. There were severe discontinuities of the ependymal lining of the lateral ventricles and subependymal rarefaction and gliosis with tau‐positive deposition.ConclusionsShunt surgery could ameliorate NPH symptoms in patients with 4‐repeat tauopathies. Careful assessments of clinical findings are necessary to predict the benefits of shunts as a therapeutic option for patients with neurodegenerative diseases coexisting with NPH.

Is the Phenotype Designation by PSP-MDS Criteria Stable Throughout the Disease Course and Consistent With Tau Distribution?

IntroductionThe MDS-PSP criteria have shown high sensitivity for the PSP diagnosis, but do not discriminate the phenotype diversity. Our purpose was to search for anatomopathological differences among PSP phenotypes resulting from the application of the MDS-PSP criteria comparing with the previous ones.MethodsThirty-four PSP cases from a single brain bank were retrospectively classified according to the criteria used by Respondek et al. in 2014 and the PSP-MDS criteria at 3 years (MDS-3y), 6 years (MDS-6y) and at the last clinical evaluation before death (MDS-last). Semiquantitative measurement of total, cortical and subcortical tau load was compared. For comparative analysis, PSP-Richardson syndrome and PSP postural instability were grouped (PSP-RS/PI) as well as the PSP atypical cortical phenotypes (PSP-Cx).ResultsApplying the Respondek's criteria, PSP phenotypes were distributed as follow: 55.9% PSP-RS/PI, 26.5% PSP-Cx, 11.8% PSP-Parkinsonism (PSP-P), and 5.9% PSP-Cerebellum. PSP-RS/PI and PSP-Cx had a higher total tau load than PSP-P; PSP-Cx showed a higher cortical tau load than PSP-RS/PI and PSP-P; and PSP-RS/PI had a higher subcortical tau load than PSP-P. Applying the MDS-3y, MDS-6y and MDS-last criteria; the PSP-RS/PI group increased (67.6, 70.6 and 70.6% respectively) whereas the PSP-Cx group decreased (8.8, and 8.8 and 11.8%). Then, only differences in total and subcortical tau burden between PSP-RS/PI and PSP-P were observed.InterpretationAfter the retrospective application of the new MDS-PSP criteria, total and subcortical tau load is higher in PSP-RS/PI than in PSP-P whereas no other differences in tau load between phenotypes were found, as a consequence of the loss of phenotypic diversity.