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

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.

Caregiver strain in progressive supranuclear palsy and corticobasal syndromes

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) progress relentlessly and lead to a need for care. Caregiving is often burdensome. Little is known about the course of caregiver burden (CB) in PSP and CBS patients. Longitudinal analysis of CB in family members caring for PSP and CBS patients. Single-center longitudinal pilot study in 68 newly diagnosed patients with probable PSP and CBS (52 Richardson’s syndrome; 1 progressive gait freezing of PSP; 15 CBS). Demographic, educational, occupational parameters, family status, motor functions (UPDRSIII, Hoehn and Yahr Score, Tinetti) and neuropsychological performance (CERAD Plus, Frontal Assessment Battery) were assessed, as well as behavioral and neuropsychiatric impairments (Frontal Behavioral Inventory, Neuropsychiatric Inventory), activities of daily living (ADL) and caregiver burden using the Caregiver Strain Index (CSI), in most patients also the Zarit Burden Interview (ZBI). Patients were followed up every 6 months for up to 2 years. Caregivers reported mild to moderate CB at baseline, which increased by 25–30% in 2 years and was significantly greater in PSP than in CBS. Risk for mental health problems increased over time, especially in female caregivers (depression). Important patient-related factors were apathy, aspontaneity, depression, irritability, disorganization, poor judgment, impairment of language, impairments in ADL, a high educational level of the patient and close family relationship. Behavioral symptoms and impaired ADL are the main patient-related factors of CB in PSP and CBS. CB can be severe and needs to be assessed repeatedly from the time of diagnosis to provide comprehensive support.

Gait Analysis in Progressive Supranuclear Palsy Phenotypes

The objective of the present study was to describe gait parameters of progressive supranuclear palsy (PSP) phenotypes at early stage verifying the ability of gait analysis in discriminating between disease phenotypes and between the other variant syndromes of PSP (vPSP) and Parkinson's disease (PD). Nineteen PSP (10 PSP-Richardson's syndrome, five PSP-parkinsonism, and four PSP-progressive gait freezing) and nine PD patients performed gait analysis in single and dual tasks. Although phenotypes showed similar demographic and clinical variables, Richardson's syndrome presented worse cognitive functions. Gait analysis demonstrated worse parameters in Richardson's syndrome compared with the vPSP. The overall diagnostic accuracy of the statistical model during dual task was almost 90%. The correlation analysis showed a significant relationship between gait parameters and visuo-spatial, praxic, and attention abilities in PSP-Richardson's syndrome only. vPSP presented worse gait parameters than PD. Richardson's syndrome presents greater gait dynamic instability since the earliest stages than other phenotypes. Computerized gait analysis can differentiate between PSP phenotypes and between vPSP and PD.

DescribePSP and ProPSP: German Multicenter Networks for Standardized Prospective Collection of Clinical Data, Imaging Data, and Biomaterials of Patients With Progressive Supranuclear Palsy

Background: The German research networks DescribePSP and ProPSP prospectively collect comprehensive clinical data, imaging data and biomaterials of patients with a clinical diagnosis of progressive supranuclear palsy. Progressive supranuclear palsy is a rare, adult-onset, neurodegenerative disease with striking clinical heterogeneity. Since now, prospective natural history data are largely lacking. Clinical research into treatment strategies has been limited due to delay in clinical diagnosis and lack of natural history data on distinct clinical phenotypes.Methods: The DescribePSP network is organized by the German Center for Neurodegenerative Diseases. DescribePSP is embedded in a larger network with parallel cohorts of other neurodegenerative diseases and healthy controls. The DescribePSP network is directly linked to other Describe cohorts with other primary diagnoses of the neurodegenerative and vascular disease spectrums and also to an autopsy program for clinico-pathological correlation. The ProPSP network is organized by the German Parkinson and Movement Disorders Society. Both networks follow the same core protocol for patient recruitment and collection of data, imaging and biomaterials. Both networks host a web-based data registry and a central biorepository. Inclusion/exclusion criteria follow the 2017 Movement Disorder Society criteria for the clinical diagnosis of progressive supranuclear palsy.Results: Both networks started recruitment of patients by the end of 2015. As of November 2020, N = 354 and 269 patients were recruited into the DescribePSP and the ProPSP studies, respectively, and N = 131 and 87 patients received at least one follow-up visit.Conclusions: The DescribePSP and ProPSP networks are ideal resources for comprehensive natural history data of PSP, including imaging data and biological samples. In contrast to previous natural history studies, DescribePSP and ProPSP include not only patients with Richardson's syndrome, but also variant PSP phenotypes as well as patients at very early disease stages, before a diagnosis of possible or probable PSP can be made. This will allow for identification and evaluation of early biomarkers for diagnosis, prognosis, and progression.

Locus Coeruleus Integrity from 7T MRI Relates to Apathy and Cognition in Parkinson’s Disease and Progressive Supranuclear Palsy

Background and ObjectivesThe loss of noradrenergic neurons in the locus coeruleus (LC) contributes to various cognitive and neuropsychiatric symptoms in Parkinson’s disease (PD) and progressive supranuclear palsy (PSP). The spatial precision of in vivo LC imaging is improved using a magnetisation transfer sequence combined with ultra-high field 7T MRI. This study aimed to test the sensitivity of LC imaging in PD and PSP, to characterise the spatial pattern of LC atrophy in patients, and its relationship to cognition and apathy.MethodsThis cross-sectional observational study recruited patients with idiopathic PD, probable PSP-Richardson’s syndrome and age-matched healthy controls (HC) via specialist clinics and volunteer registries. All participants underwent clinical assessments for cognition and apathy, and high-resolution (0.08 mm3) LC scans. To quantify LC integrity, the contrast-to-noise ratio (CNR) relative to a pons reference region was calculated and extracted using a probabilistic atlas. Subregional mean CNRs were summarised to test group differences and to correlate LC integrity with apathy and cognition scores. LC clusters were identified to confirm the spatial pattern of the effect (threshold free cluster enhancement, 10000 permutations, p<0.05, corrected for family-wise error).ResultsTwenty-five patients with PD, 14 with PSP and 24 controls with completed dataset were included in the study. Patients with PSP were more impaired on global cognition and apathy scores, compared to controls and PD. Clusters with reduced contrast were observed in the caudal LC for both PD and PSP patients relative to controls (HC>PD, right caudal LC, 37 voxels; HC>PSP, bilateral caudal LC, 206 voxels). PSP and PD patients showed similar levels of LC degeneration, but this was more extensive in PSP. Across both disease groups, LC integrity was associated with cognitive performance (MoCA: F(1,37)=5.339, p=0.027, bilateral LC, 200 voxels; ACE-R: F(1,37)=4.297, p=0.045, left LC, 70 voxels) and apathy (Apathy Scale: F(1,37)=4.335, p=0.044, left LC, 99 voxels).DiscussionWe confirm the sensitivity of 7T LC imaging to detect sub-regional LC changes in PD and PSP. The relationship between LC integrity and non-motor symptoms highlights the potential for noradrenergic therapeutic strategies to ameliorate cognitive and behavioural features of PD and PSP.

Validation of the new pathology staging system for progressive supranuclear palsy

Progressive 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.

Synaptic loss in primary tauopathies revealed by [11C]UCB-J positron emission tomography

BackgroundSynaptic loss is a prominent and early feature of many neurodegenerative diseases.ObjectivesWe tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP-Richardson’s syndrome) and amyloid-negative corticobasal syndrome (CBS).MethodsForty four participants (15 CBS, 14 PSP, and 15 age-/sex-/education-matched controls) underwent positron emission tomography (PET) with the radioligand [11C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), a marker of synaptic density; participants also had 3T magnetic resonance imaging and clinical and neuropsychological assessment.ResultsNine CBS patients had negative amyloid biomarkers determined by [11C]PiB PET and hence were deemed likely to have corticobasal degeneration (CBD). Patients with PSP-Richardson’s syndrome and amyloid-negative CBS were impaired in executive, memory and visuospatial tasks. [11C]UCB-J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala and subcortical structures in both PSP and CBD patients compared to controls (p<0.01), with median reductions up to 50%, consistent with post mortem data. Reductions of 20-30% were widespread even in the areas of the brain with minimal atrophy. There was a negative correlation between global [11C]UCB-J binding and the PSP and CBD rating scales (R= −0.61 p<0.002, R= −0.72 p<0.001, respectively) and a positive correlation with the revised Addenbrookes Cognitive Examination (R=0.52, p=0.01).ConclusionsWe confirm severe synaptic loss in PSP and CBD in proportion to disease severity, providing critical insight into the pathophysiology of primary degenerative tauopathies. [11C]UCB-J may facilitate treatment strategies for disease-modification, synaptic maintenance or restoration.

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

The 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.