scholarly journals Validation of the new pathology staging system for progressive supranuclear palsy

2021 ◽  
Author(s):  
Mayen Briggs ◽  
Kieren SJ Allinson ◽  
Maura Malpetti ◽  
Maria Grazia Spillantini ◽  
James Benedict Rowe ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Staging System ◽  
Clinical Severity ◽  
Potential Association ◽  
Cortical Regions ◽  
Operational Criteria ◽  
Richardson’S Syndrome ◽  
Addenbrooke’S Cognitive Examination

AbstractProgressive supranuclear palsy (PSP) is a neurodegenerative disorder associated with neuroglial accumulation of 4-repeat tau protein. Kovacs et al. have recently proposed a new semi-quantitative staging system to categorise the severity of PSP pathology, using the distribution of tau aggregates as it progresses from subcortical to cerebellar and cortical regions. Here, we test the new PSP pathology staging system in an independent series of PSP, and test the potential association between pathology stage and clinical severity at death. We include tissue from 35 people with a clinical diagnosis of PSP (including N=25 with Richardson’s syndrome and N=10 with other phenotypes). Donors had attended longitudinal clinical studies at the Cambridge Centre Parkinson-plus including assessment of clinical severity by the PSP rating scale (PSPRS) and cognitive performance by the revised Addenbrooke’s Cognitive Examination (ACE-R). We rated tau pathology from none-to-severe in six regions. We focused on (I) astrocytic tau inclusions in striatum, frontal and occipital regions, and (II) neuronal and oligodendroglia tau inclusions in globus pallidus, subthalamic nucleus, and cerebellum. Thirty-two cases (91%) readily conformed to the new staging system, ranging from stage 2 to 6. Staging system applied to brains from people with different clinical phenotypes of PSP. Neuropathology stages correlated with clinical severity at death using both PSPRS and ACE-R, weighted for the interval between last assessment and donation. Our study supports the proposed sequential distribution of tau aggregates in PSP pathology, and the hypothesised relationship between clinical and neuropathological severity. For future studies, in order to standardise rating between centres, we propose a set of operational criteria for region-specific thresholds or tau burden, and a visual guide.

scholarly journals Clinical progression of progressive supranuclear palsy: impact of trials bias and phenotype variants

2021 ◽  
Author(s):  
Duncan Street ◽  
Maura Malpetti ◽  
Timothy Rittman ◽  
Boyd C P Ghosh ◽  
Alexander G Murley ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Progressive Supranuclear Palsy ◽  
Trial Design ◽  
Mini Mental State Examination ◽  
Rating Scale ◽  
Clinical Progression ◽  
Eligibility Criteria ◽  
Richardson’S Syndrome ◽  
State Examination ◽  
Addenbrooke’S Cognitive Examination

Abstract Progressive supranuclear palsy causes diverse clinical presentations, including classical Richardson’s syndrome and several variant phenotypes. Clinical trials of disease-modifying therapies have recently been completed, with more planned for the next two 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 United Kingdom healthcare service. Longitudinal clinical data from people with Richardson’s 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 Addenbrooke’s Cognitive Examination. Subgroup analyses considered patients meeting recent phase II trial entry criteria and patients with neuropathological confirmation. 227 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 Richardson’s syndrome at the outset, twenty-five had cortical variant presentations (13%, frontal, corticobasal, speech and language variants) and twenty-eight had subcortical variant presentations (14%, parkinsonism, postural instability and gait freezing variants). Across all participants, annual progression in Richardson’s syndrome was faster than variant phenotypes on the Mini-Mental State Examination (-1.8 vs -0.9/year, p = 0.005) and revised Addenbrooke’s Cognitive Examination (-5.3 vs -3.0/year, p = 0.01) but not the Progressive Supranuclear Palsy Rating Scale (9.0 vs 7.1/year, p = 0.2) nor the modified Progressive Supranuclear Palsy Rating Scale (2.7 vs 2.3/year, p = 0.4). However, for those with more than one years’ follow-up, a significant difference was observed between Richardson’s syndrome and variant phenotypes in Progressive Supranuclear Palsy Rating Scale (8.7 vs 6.3/year, p = 0.04). Survival was longer in variant phenotypes than Richardson’s syndrome (7.3[±3.9] vs 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 vs 6.1/year, p = 0.001). In conclusion, phenotypes other than Richardson’s 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.

scholarly journals Peripapillary retinal nerve fiber layer thinning in patients with progressive supranuclear palsy

2021 ◽  
Author(s):  
Kyung Ah Woo ◽  
Joo Young Shin ◽  
Heejung Kim ◽  
Jeeyun Ahn ◽  
Beomseok Jeon ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Nerve Fiber ◽  
Retinal Nerve Fiber Layer ◽  
Rating Scale ◽  
Brain Mri ◽  
Clinical Severity ◽  
Fiber Layer ◽  
Brain Volumes ◽  
Nerve Fiber Layer ◽  
Retinal Nerve Fiber

Abstract Objectives To investigate peripapillary retinal nerve fiber layer (pRNFL) changes in patients with progressive supranuclear palsy (PSP). Methods We included 21 PSP patients (36 eyes) who underwent peripapillary optical coherence tomography (OCT) scans at 2.5 ± 1.3 years of disease, without ophthalmologic co-morbidities. We compared pRNFL thicknesses in PSP eyes with age-matched 22 controls (22 eyes) using generalized estimating equation model adjusting for intra-subject inter-eye correlations, age and sex. We also analyzed the correlation between the pRNFL thickness and clinical severity using Spearman’s correlation. In twelve PSP patients with 3 T brain MRI volumetric scan within 1 year of OCT exam, we investigated the correlation between the pRNFL thickness and brain atrophy using Pearson’s correlation. Results PSP patients had global pRNFL thinning compared to controls (beta = − 6.436, p = 0.025). Global pRNFL thickness correlated with Hoehn & Yahr stages (r = − 0.487, p = 0.025), and nasal pRNFL thinning showed a trend of correlation (uncorrected p < 0.05). Exploratory correlation analysis between global pRNFL thickness and nonmotor items in the PSP rating scale showed a trend toward association with sleep disturbances (uncorrected p = 0.008) and urinary incontinence (uncorrected p = 0.031), although not significant after Bonferroni correction (all 28 items). The patients had significant atrophy in the posterior cingulate cortex, third ventricle, pallidum, and midbrain with reduced midbrain-to-pons ratio, but no correlation was found between pRNFL thickness and brain volumes. Conclusion The pRNFL seems to be affected in PSP, which is more severe with advanced disease stages. Retinal investigation in a larger longitudinal cohort would help elucidate the pathophysiological role of retinal thinning in PSP.

scholarly journals Prediction of the Clinical Severity of Progressive Supranuclear Palsy by Diffusion Tensor Imaging

2019 ◽  
Vol 9 (1) ◽  
pp. 40 ◽  
Author(s):  
Yao-Liang Chen ◽  
Xiang-An Zhao ◽  
Shu-Hang Ng ◽  
Chin-Song Lu ◽  
Yu-Chun Lin ◽  
...  
Keyword(s):  
Machine Learning ◽  
Diffusion Tensor Imaging ◽  
Progressive Supranuclear Palsy ◽  
Rating Scale ◽  
Diffusion Tensor ◽  
Learning Algorithm ◽  
Mean Diffusivity ◽  
Feature Reduction ◽  
Clinical Severity ◽  
Machine Learning Algorithm

Progressive supranuclear palsy (PSP) is characterized by a rapid and progressive clinical course. A timely and objective image-based evaluation of disease severity before standard clinical assessments might increase the diagnostic confidence of the neurologist. We sought to investigate whether features from diffusion tensor imaging of the entire brain with a machine learning algorithm, rather than a few pathogenically involved regions, may predict the clinical severity of PSP. Fifty-three patients who met the diagnostic criteria for probable PSP were subjected to diffusion tensor imaging. Of them, 15 underwent follow-up imaging. Clinical severity was assessed by the neurological examinations. Mean diffusivity and fractional anisotropy maps were spatially co-registered, normalized, and parcellated into 246 brain regions from the human Brainnetome atlas. The predictors of clinical severity from a stepwise linear regression model were determined after feature reduction by the least absolute shrinkage and selection operator. Performance estimates were obtained using bootstrapping, cross-validation, and through application of the model in the patients who underwent repeated imaging. The algorithm confidently predicts the clinical severity of PSP at the individual level (adjusted R2: 0.739 and 0.892, p < 0.001). The machine learning algorithm for selection of diffusion tensor imaging-based features is accurate in predicting motor subscale of unified Parkinson’s disease rating scale and postural instability and gait disturbance of PSP.

scholarly journals Sodium selenate as a disease-modifying treatment for progressive supranuclear palsy: protocol for a phase 2, randomised, double-blind, placebo-controlled trial

BMJ Open ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. e055019
Author(s):  
Lucy Vivash ◽  
Kelly L Bertram ◽  
Charles B Malpas ◽  
Cassandra Marotta ◽  
Ian H Harding ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Controlled Trial ◽  
Primary Study ◽  
Sodium Selenate ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Disease Modifying ◽  
The Brain

IntroductionProgressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP.Methods and analysisThis will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain–3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures.Ethics and disseminationThe study was approved by the Alfred Health Ethics Committee (594/20). Each participant or their legally authorised representative and their study partner will provide written informed consent at trial commencement. The results of the study will be presented at national and international conferences and published in peer-reviewed journals.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12620001254987).

scholarly journals Predicting Longitudinal Disease Severity for Individuals with Parkinson’s Disease using Functional MRI and Machine Learning Prognostic Models

2020 ◽  
Author(s):  
Kevin P. Nguyen ◽  
Vyom Raval ◽  
Alex Treacher ◽  
Cooper Mellema ◽  
Frank Yu ◽  
...  
Keyword(s):  
Machine Learning ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Severity ◽  
Clinical Decision Making ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Clinical Severity ◽  
Predictive Values ◽  
Updrs Score

AbstractParkinson’s disease is the second most common neurodegenerative disorder and is characterized by the loss of ability to control voluntary movements. Predictive biomarkers of progression in Parkinson’s Disease are urgently needed to expedite the development of neuroprotective treatments and facilitate discussions about disease prognosis between clinicians and patients. Resting-state functional magnetic resonance imaging (rs-fMRI) shows promise in predicting progression, with derived measures, including regional homogeneity (ReHo) and fractional amplitude of low frequency fluctuations (fALFF), having been previously been associated with current disease severity. In this work, ReHo and fALFF features from 82 Parkinson’s Disease subjects are used to train machine learning predictors of baseline clinical severity and progression at 1 year, 2 years, and 4 years follow-up as measured by the Movement Disorder Society Unified Depression Rating Scale (MDS-UPDRS) score. This is the first time that rs-fMRI and machine learning have been combined to predict future disease progression. The machine learning models explain up to 30.4% (R2 = 0.304) of the variance in baseline MDS-UPDRS scores, 55.8% (R2 = 0.558) of the variance in year 1 scores, and 47.1% (R2 = 0.471) of the variance in year 2 scores with high statistical significance (p < 0.0001). For distinguishing high- and low-progression individuals (MDS-UPDRS score above or below the median), the models achieve positive predictive values of up to 71% and negative predictive values of up to 84%. The models learn patterns of ReHo and fALFF measures that predict better and worse prognoses. Higher ReHo and fALFF in regions of the default motor network predicted lower current severity and lower future progression. The rs-fMRI features in the temporal lobe, limbic system, and motor cortex were also identified as predictors. These results present a potential neuroimaging biomarker that accurately predicts progression, which may be useful as a clinical decision-making tool and in future trials of neuroprotective treatments.

scholarly journals PET markers of tau and neuroinflammation are co-localized in progressive supranuclear palsy

2019 ◽  
Author(s):  
Maura Malpetti ◽  
Luca Passamonti ◽  
Timothy Rittman ◽  
P. Simon Jones ◽  
Patricia Vázquez Rodríguez ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Microglial Activation ◽  
Principal Component ◽  
Brain Regions ◽  
Clinical Severity ◽  
Binding Potential ◽  
Tau Pathology ◽  
Richardson’S Syndrome ◽  
The Relationship

AbstractBackgroundProgressive Supranuclear Palsy (PSP) is associated with tau-protein aggregation and neuroinflammation, but it remains unclear whether these pathogenic processes are related in vivo.ObjectivesWe examined the relationship between tau pathology and microglial activation using [18F]AV-1451 (indexing tau burden) and [11C]PK11195 (microglial activation) PET in n=17 patients with PSP-Richardson’s syndrome.MethodsNon-displaceable binding potential (BPND) for each ligand was quantified in 83 regions of interest (ROIs). [18F]AV-1451 and [11C]PK11195 BPND values were correlated across all ROIs. The anatomical patterns of [18F]AV-1451 and [11C]PK11195 binding co-localization was determined across sets of regions derived from principal component analyses (PCAs). Finally, PCA-derived brain patterns of tau pathology and neuroinflammation were linked to clinical severity.Results[18F]AV-1451 and [11C]PK11195 binding were positively related across all ROIs (r=0.577, p<0.0001). PCAs identified four components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [18F]AV-1451 and [11C]PK11195 components were found in sub-cortical (r=0.769, p<0.0001) and cortical components(r=0.836, p<0.0001). PCA-derived components reflecting tau burden (r=0.599, p=0.011) and neuroinflammation (r=0.713, p=0.001) in sub-cortical areas related to disease severity.ConclusionsWe show that tau pathology and neuroinflammation co-localize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine how these molecular pathologies are causally linked, we suggest that the combination of tau- and immune-oriented strategies may be useful for effective disease-modifying treatments in PSP.

scholarly journals Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity

2020 ◽  
Author(s):  
Sanne Simone Kaalund ◽  
Luca Passamonti ◽  
Kieren SJ Allinson ◽  
Alexander G Murley ◽  
Trevor W Robbins ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Progressive Supranuclear Palsy ◽  
Disease Severity ◽  
Neuronal Loss ◽  
Clinical Severity ◽  
Adaptive Behaviour ◽  
Clinical Heterogeneity ◽  
Tau Pathology ◽  
Wide Range ◽  
Richardson’S Syndrome

AbstractThe locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson’s syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP.We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson’s syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients.We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions.Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.

scholarly journals Change in the plasma proteome associated with canine cognitive dysfunction syndrome (CCDS) in Thailand

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Sataporn Phochantachinda ◽  
Boonrat Chantong ◽  
Onrapak Reamtong ◽  
Duangthip Chatchaisak
Keyword(s):  
Cognitive Dysfunction ◽  
Plasma Proteins ◽  
Protein Identification ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Underlying Mechanism ◽  
Population Based ◽  
Diagnostic Biomarker ◽  
Adult Group ◽  
Proteomics Analysis

Abstract Background Canine cognitive dysfunction syndrome (CCDS) is a progressive neurodegenerative disorder found in senior dogs. Due to the lack of biological markers, CCDS is commonly underdiagnosed. The aim of this study was to identify potential plasma biomarkers using proteomics techniques and to increase our understanding of the pathogenic mechanism of the disease. Plasma amyloid beta 42 (Aβ42) has been seen to be a controversial biomarker for CCDS. Proteomics analysis was performed for protein identification and quantification. Results Within CCDS, ageing, and adult dogs, 87 proteins were identified specific to Canis spp. in the plasma samples. Of 87 proteins, 48 and 41 proteins were changed in the ageing and adult groups, respectively. Several distinctly expressed plasma proteins identified in CCDS were involved in complement and coagulation cascades and the apolipoprotein metabolism pathway. Plasma Aβ42 levels considerably overlapped within the CCDS and ageing groups. In the adult group, the Aβ42 level was low compared with that in the other groups. Nevertheless, plasma Aβ42 did not show a correlation with the Canine Cognitive Dysfunction Rating scale (CCDR) score in the CCDS group (p = 0.131, R2 = 0.261). Conclusions Our present findings suggest that plasma Aβ42 does not show potential for use as a diagnostic biomarker in CCDS. The nano-LC-MS/MS data revealed that the predictive underlying mechanism of CCDS was the co-occurrence of inflammation-mediated acute phase response proteins and complement and coagulation cascades that partly functioned by apolipoproteins and lipid metabolism. Some of the differentially expressed proteins may serve as potential predictor biomarkers along with Aβ42 in plasma for improved CCDS diagnosis. Further study in larger population-based cohort study is required in validation to define the correlation between protein expression and the pathogenesis of CCDS.

scholarly journals Evaluation of fecal microbiota transplantation in Parkinson's disease patients with constipation

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiao-yi Kuai ◽  
Xiao-han Yao ◽  
Li-juan Xu ◽  
Yu-qing Zhou ◽  
Li-ping Zhang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Motor Symptoms ◽  
Gastrointestinal Dysfunction ◽  
Before And After ◽  
Non Motor Symptoms

AbstractParkinson’s disease (PD) is a neurodegenerative disorder and 70–80% of PD patients suffer from gastrointestinal dysfunction such as constipation. We aimed to assess the efficacy and safety of fecal microbiota transplantation (FMT) for treating PD related to gastrointestinal dysfunction. We conducted a prospective, single- study. Eleven patients with PD received FMT. Fecal samples were collected before and after FMT and subjected to 16S ribosomal DNA (rDNA) gene sequencing. Hoehn-Yahr (H-Y) grade, Unified Parkinson's Disease Rating Scale (UPDRS) score, and the Non-Motion Symptom Questionnaire (NMSS) were used to assess improvements in motor and non-motor symptoms. PAC-QOL score and Wexner constipation score were used to assess the patient's constipation symptoms. All patients were tested by the small intestine breath hydrogen test, performed before and after FMT. Community richness (chao) and microbial structure in before-FMT PD patients were significantly different from the after-FMT. We observed an increased abundance of Blautia and Prevotella in PD patients after FMT, while the abundance of Bacteroidetes decreased dramatically. After FMT, the H-Y grade, UPDRS, and NMSS of PD patients decreased significantly. Through the lactulose H2 breath test, the intestinal bacterial overgrowth (SIBO) in PD patients returned to normal. The PAC-QOL score and Wexner constipation score in after-FMT patients decreased significantly. Our study profiles specific characteristics and microbial dysbiosis in the gut of PD patients. FMT might be a therapeutic potential for reconstructing the gut microbiota of PD patients and improving their motor and non-motor symptoms.

scholarly journals A Modified Progressive Supranuclear Palsy Rating Scale

2021 ◽  
Author(s):  
Marie‐Therese Grötsch ◽  
Gesine Respondek ◽  
Carlo Colosimo ◽  
Yaroslau Compta ◽  
Jean Christophe Corvol ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Rating Scale
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