Progression of two Progressive Supranuclear Palsy phenotypes with comparable initial disability

Ziel/Aim Progressive supranuclear palsy (PSP) is a 4-repeat (4R) tauopathy and region-specific tau deposits establish the neuropathological diagnosis of “definite PSP” post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers to validate the specific presence of the target before therapy initiation. The novel second generation tau-PET ligand 18F-PI2620 proved absent off-target binding to monoamine oxidases and high affinity to 3/4R tau in Alzheimer’s disease (AD). The aim of this multicenter-evaluation was to investigate 18F-PI2620 in patients with suspected 4R tau pathology in clinically diagnosed PSP.

Considerable evidence suggests that midbrain-based magnetic resonance Parkinsonism index (MRPI) measurements are reliable biomarkers for the diagnosis of progressive supranuclear palsy (PSP). However, the longitudinal atrophy pattern of PSP and potential differences in change rates among PSP phenotypic spectrum remain unclear. This study aims to investigate the longitudinal changes of MRPI measurements and explore their potential role in PSP phenotype progression monitoring. Thirty-six patients with PSP-Richardson's syndrome (PSP-RS), 21 patients with variant PSP (vPSP), and 21 healthy controls (HCs) with longitudinal MRI and clinical follow-up were enrolled. Midbrain-based morphometric measurements and the corresponding annual percentage changes (APCs) were measured and further used to evaluate the associations with disease progression. Significant differences in midbrain-based morphometric biomarkers were observed both at baseline and longitudinal trajectories between PSP and HC groups, but no significant differences were found between PSP-RS and vPSP subgroups. Baseline comprehensive measurements were significantly associated with the baseline PSP rating scale (PSPrs) in all PSP and PSP phenotypes. The APC of MRPI was significantly associated with the APC of PSPrs in all PSP (r = 0.267, p = 0.046) and the PSP-RS subgroup (r = 0.386, p = 0.020). This study characterizes the longitudinal atrophy trajectory of PSP phenotypes and the significant associations between morphometric measurements and disease severity. Dissecting the causal associations among core 4R-tau, dopamine, and subsequent atrophy trajectories may enhance the application of these biomarkers for phenotype attribution. Questions The use of midbrain-based MRPI measurements to assess the longitudinal prognosis of the PSP phenotype remains uncertain. Findings Significant differences in midbrain-based morphometric biomarkers were observed both at baseline and longitudinal trajectories between PSP and health control groups. Clinical relevance Midbrain-based morphometric measurements hold promise as potential radiological biomarkers for monitoring PSP disease progression and assessment.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off-label in the hope of slowing disease progression. Results from these experiences are seldom shared, which limits evidence-based knowledge to guide future treatment decisions. To describe an open-label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP-Richardson's syndrome (PSP-RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies. For 6 months, 10 PSP-RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP-RS patients from the davunetide clinical trial and the 4-Repeat Tauopathy Neuroimaging Initiative. Salsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation [SD]) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (-0.07 ± 0.03), young plasma (-0.06 ± 0.03), and historical controls (-0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint. Neither salsalate nor young plasma had a detectable effect on disease progression in PSP-RS. Focused open-label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP-directed therapies.

Progressive supranuclear palsy (PSP) is characterized by progressive atrophy of brainstem, subcortical, and frontal regions. It is unknown whether longitudinal atrophy patterns differ between PSP-Richardson syndrome (PSP-RS) and cortical and subcortical clinical variants of PSP and whether atrophy rates could be useful outcome measures for treatment trials. We aimed to determine whether regional rates of atrophy differ across PSP clinical variants and determine sample size estimates for clinical treatment trials. We identified participants with PSP-RS, PSP-cortical, or PSP-subcortical variants recruited by the Neurodegenerative Research Group who underwent 2 annual 3T MRI scans. Volumes were calculated for 10 regions of interest, and mixed-effects regression analysis was performed to compare annualized rates of atrophy across groups, accounting for confounders. Sample sizes required to power placebo-controlled treatment trials to detect a 20% treatment effect with 80% power were calculated for rates of atrophy and clinical metrics, including the PSP Rating Scale. Fifty patients with PSP-RS (baseline age = 69 [interquartile range 64 to 75], 46% female), 18 with PSP-cortical (74 [70 to 76], 50% female), 20 with PSP-subcortical (71 [67 to 77], 60% female), and 32 controls (69 [66 to 72], 72% female) were included. Rates of midbrain, cerebellar dentate, and subthalamic atrophy were greater in all PSP variants than in controls. The PSP-RS group showed greater midbrain atrophy rates than PSP-subcortical (-1.6% difference [95% CI -2.4 to -0.7], p < 0.001) and PSP-cortical (-1.1% [-2 to -0.2], p = 0.02) groups. The PSP-cortical group showed greater rates of pallidum (12% [2.7 to 21], p = 0.02), putamen (2.1% [0.4 to 3.8], p = 0.02), and caudate (1.6% [0.1 to 3], p = 0.04) atrophy than the PSP-RS group. PSP-RS and PSP-cortical groups showed greater rates of superior frontal (2.2% [0 to 4.3], p = 0.049, and 4.7% [1.9 to 7.4], p = 0.002, respectively) and precentral (2.6% [0.1 to 5.1], p = 0.046, and 4.3% [1 to 7.5], p = 0.01, respectively) atrophy than controls, with no differences between variants. The smallest sample size estimates were obtained using a metric combining the PSP Rating Scale and the best-performing regional volume, providing sample size estimates of 107 participants/arm for PSP-RS, 88 for PSP-cortical, and 368 for PSP-subcortical. Regional patterns of brain atrophy differ across PSP clinical variants, although midbrain atrophy was common in all variants. Sample size estimates suggest that combining the PSP Rating Scale and targeted MRI volumes provides the optimum outcome measure for clinical treatment trials recruiting patients with PSP clinical variants.

Fatigue is a common and disabling non-motor symptom (NMS) of Parkinson’s disease (PD); however, it has been poorly understood in patients with progressive supranuclear palsy (PSP). We investigated the association between fatigue, clinical features, and other NMS in patients with probable PSP. In 72 probable PSP patients, fatigue was investigated using the Parkinson Fatigue Scale (PFS). Further, all patients were evaluated using the PSP rating scale (PSPRS), Beck Depression Inventory (BDI), Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), PD Sleep Scale (PDSS), NMS scale (NMSS), PD Questionnaire-39 summary index (PDQ-39 SI), and Scale for outcomes in PD-Autonomic (SCOPA-AUT). The prevalence of fatigue assessed by PFS was 38.9% (28/72) in patients with PSP. The secondary fatigue was defined as fatigued patients with depression and/or sleep disturbances. We divided the patients into primary (n = 15), secondary (n = 13), and non-fatigue groups. There were no differences in age, sex, disease duration, and PSPRS, PDSS, MMSE, and FAB scores among the three groups. The primary fatigue group had higher scores in PDQ-39 SI compared to the non-fatigue group. The secondary fatigue group showed higher scores in NMSS, PDQ-39 SI, and SCOPA-AUT compared to the non-fatigue group. PFS was positively correlated with NMSS and PDQ-39 SI and SCOPA-AUT. Fatigue is common in patients with PSP and is associated with the NMS and the quality of life in these patients. The present study provides meaningful insight into fatigue in patients with PSP.

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

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are severe neurodegenerative disorders lacking disease-modifying treatments and validated biomarkers. Clinical trials face challenges due to phenotypic overlap and imperfect clinicopathological correlations. MRI-derived models have shown to accurately predict PSP and CBD pathology in a large autopsy-confirmed cohort (Illán-Gala et al., JAMA Network Open, 2022). This study examines how participant selection based on MRI models and imaging outcomes impacts sample size estimations in hypothetical clinical trials. Eighty-four participants from the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) with baseline and longitudinal MRI data and clinical assessments were included. Diagnoses comprised Richardson syndrome (RS, 61%) and corticobasal syndrome (CBS, 30%) without Alzheimer's disease. MRI-derived models predicted PSP, CBD, or other pathologies (MRI-PSP, MRI-CBD, MRI-Other) according to baseline MRI. Cortical thickness and volume measures were derived from MRI data using Freesurfer and employed to identify an optimal MRI-signature of regions showing the highest effect size on atrophy over 12 months using linear mixed-effects models. Disease progression was also measured with PSP Rating Scale (PSPRS). Sample sizes required to detect a 30% reduction in mean change at 12 months were calculated for hypothetical clinical trials. MRI predicted PSP, CBD, and other pathologies in 46%, 26%, and 27% of participants, respectively. Among RS diagnoses, 31 (61%) were classified as MRI-PSP; among CBS, 6 (24%) were MRI-CBD. MRI-signature regions for PSP progression included midbrain, superior-temporal, and rostral-middle-frontal thickness. For CBD, key regions included midbrain and pons volumes, superior-frontal, and entorhinal thickness. In a hypothetical PSP trial, selection criteria based on clinical diagnosis required 336 participants using PSPRS as outcome, while MRI-based diagnosis with MRI-signature as outcome reduced the sample size to 121 (64% decrease). For a CBS trial, the sample size reduced from 1301 participants if inclusion was based on clinical diagnosis to 160 using MRI-based selection and outcomes. Selecting participants with increased diagnostic certainty for PSP and CBD based on baseline MRI, combined with using MRI measures as outcomes could enhance the efficiency of future phase 2 clinical trials for 4R tauopathies. We plan to replicate these results in the Davunetide trial cohort.

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.

Typically, progressive supranuclear palsy (PSP) is clinically characterized by slow vertical saccades or supranuclear gaze palsy, levodopa-resistant parkinsonism with predominant axial symptoms, and cognitive executive impairment. Over the past decades, various PSP phenotypes, including PSP with predominant parkinsonism, PSP with corticobasal syndrome, PSP with progressive gait freezing, and PSP with predominant frontal dysfunction, have been identified from pathologically confirmed cases. Expanding knowledge led to new diagnostic criteria for PSP that with increased disease awareness led to increased PSP prevalence estimates. The identification of environmental and modifiable risk factors creates an opportunity to intervene and delay the onset of PSP or slow disease progression. To date, despite the increasing number of publications assessing risk factors for PSP, few articles have focused on environmental and lifestyle risk factors for this disorder. In this article, we reviewed the literature investigating the relationship between PSP and several environmental and other modifiable lifestyle risk factors. In our review, we found that exposures to toxins related to diet, metals, well water, and hypertension were associated with increased PSP risk. In contrast, higher education and statins may be protective. Further case-control studies are encouraged to determine the exact role of these factors in the etiopathogenesis of PSP, which in turn would inform strategies to prevent and reduce the burden of PSP.

Progressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy characterized by early postural instability and vertical gaze palsy. Mitochondrial dysfunctions have been increasingly implicated in the pathogenesis of neurodegenerative disorders, including PSP. We investigated mitochondrial DNA copy number (mtDNA-CN) alterations in the peripheral blood of PSP patients, assessing its potential as a biomarker for disease onset and progression. We measured mtDNA-CN in a cohort of clinically diagnosed PSP patients and age-matched healthy controls using quantitative real-time PCR. We evaluated differences across clinical phenotypes and age groups. PSP patients exhibited a significant reduction in ND3-CN compared to healthy controls (p < 0.0001). This depletion remained consistent across age groups, suggesting that mitochondrial impairment in PSP is independent of physiological aging. Although not statistically significant, ND3-CN levels were lower in PSP-parkinsonism (PSP-P) patients compared to those with Richardson's syndrome (PSP-RS). Interestingly, in PSP-RS patients, ND3-CN levels tended to increase with age, potentially reflecting an age-related compensatory mitochondrial response to chronic neuroinflammation. Our findings support the involvement of mitochondrial dysfunction in PSP pathogenesis, suggesting that peripheral mtDNA-CN may serve as a non-invasive biomarker for disease monitoring. Further studies in larger cohorts are warranted to validate its prognostic potential in different PSP phenotypes.

Rapid eye movement sleep behavior disorder (RBD) is increasingly recognized in patients with tauopathies, but its significance and underpinnings remain unclear. To address this gap, we investigated the prevalence of self-reported RBD in patients with progressive supranuclear palsy (PSP) and explored its clinical and imaging correlates using 18F-florzolotau PET imaging. We consecutively enrolled patients meeting the 2017 Movement Disorder Society clinical criteria for PSP at a Chinese tertiary hospital between May 2019 and March 2022. Patients underwent comprehensive clinical assessments and 18F-florzolotau PET to investigate tau deposition patterns. The presence of self-reported RBD was identified using the RBD Single-Question Screen, while its frequency was retrospectively collected from medical history. We examined 148 patients recruited in the ongoing Progressive Supranuclear Palsy Neuroimage Initiative cohort. Self-reported RBD was identified in 18.2% of the participants (27/148). Patients with PSP-Richardson syndrome and PSP-parkinsonism reported the highest frequencies of self-reported RBD (21.7% and 18.5%, respectively), compared with PSP-progressive gait freezing (9.7%). While age and sex were similar in patients with and without self-reported RBD, the former group exhibited greater disease severity, as indicated by higher PSP Rating Scale (PSPrs) scores (38.0 vs 27.0, effect size = 0.256, p = 0.002). Furthermore, patients with RBD had significantly higher 18F-florzolotau binding in the locus coeruleus (LC) (1.50 vs 1.38, effect size = 0.231, p = 0.003), which remained significant after false discovery rate correction (p = 0.042). The frequency of RBD was found to be correlated with tau pathology in the LC (n = 8, r = 0.752, p = 0.002). Notably, the presence of self-reported RBD symptoms mediated the relationship between LC tau pathology and PSPrs total scores (proportion-mediated = 2.09%, 95% CI 0.01%-10.00%, p = 0.044). Approximately one-fifth of patients with PSP reported RBD and exhibited more severe motor and nonmotor symptoms. The elevated 18F-florzolotau binding in the LC and its association with the presence of RBD symptoms underscore the critical role of tau pathology in disrupting sleep-regulating neural circuits. Future studies with larger sample sizes should incorporate polysomnography in patients with PSP with self-reported RBD to further elucidate this relationship.

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.

To date, pharmacological treatment options for progressive supranuclear palsy (PSP), a neurodegenerative tauopathy, are limited. The MAO-B inhibitor rasagiline has shown neuroprotective effects in preclinical models of neurodegeneration. To evaluate the safety, tolerability and therapeutic effect of rasagiline on symptom progression in PSP. In this 1-year randomized, double-blind, placebo-controlled trial, 44 patients fulfilling the NINDS-PSP criteria were randomized to 1mg/d rasagiline or placebo. The combined primary endpoint included symptom progression as measured by the PSP rating scale (PSP-RS) and the requirement of L-dopa rescue medication. Secondary endpoints included Schwab and England Activities of Daily Living (SEADL), Montgomery-Åsberg Depression Rating Scale, Mini Mental State Examination, Frontal Assessment Battery and posturographic measurements. Of the 44 patients randomized, 26 completed the trial per protocol. Rasagiline was well tolerated, with a slight increase of known side effects (hallucinations, ventricular extrasystoles). No effect on the primary endpoint (p=0.496) was detected. Symptom progression averaged at 11.2 (rasagiline) and 10.8 (placebo) points per year (ΔPSP-RS). No difference was seen in SEADL, depression, cognitive function, frontal executive function and posturographic measurements. Post hoc analyses of PSP-RS subdomains indicate a potential beneficial effect in the "limb motor" subdomain, whereas performance appeared lower in the "mentation" and "history" subdomains in the treatment group. While rasagiline is well tolerated in PSP, a beneficial effect on overall symptom progression was not detected. Post hoc analyses suggest the implementation of more specific endpoints in future studies.

Frontal hypometabolism on FDG-PET is observed in progressive supranuclear palsy (PSP), although it is unclear whether it is a feature of all PSP clinical variants and hence whether it is a useful diagnostic feature. We aimed to compare the frequency, severity, and pattern of frontal hypometabolism across PSP variants and determine whether frontal hypometabolism is related to clinical dysfunction. Frontal hypometabolism in prefrontal, premotor, and sensorimotor cortices was visually graded on a 0-3 scale using CortexID Z-score images in 137 PSP patients. Frontal asymmetry was recorded. Severity scores were used to categorize patients as premotor-predominant, prefrontal-predominant, sensorimotor-predominant, mixed-predominance, or no regional predominance. Frontal ratings were compared across PSP clinical variants, and Spearman correlations were used to assess relationships with the Frontal Assessment Battery (FAB). 97% showed evidence of frontal hypometabolism which was most common (100%) in the speech-language (PSP-SL), corticobasal (PSP-CBS), and frontal (PSP-F) variants and least common in the progressive gait freezing (PSP-PGF) variant (73%). PSP-SL and PSP-CBS showed more severe hypometabolism than Richardson's syndrome (PSP-RS), Parkinsonism (PSP-P), and PSP-PGF. A premotor-predominant pattern was most common in PSP-SL and PSP-CBS, with more mixed patterns in the other variants. Hypometabolism was most commonly asymmetric in PSP-SL, PSP-P, PSP-F and PSP-CBS. Worse hypometabolism in nearly all frontal regions correlated with worse scores on the FAB. Frontal hypometabolism is a common finding in PSP, although it varies in severity and pattern across PSP variants and will likely be the most diagnostically useful in PSP-SL and PSP-CBS.

[18F]flortaucipir PET imaging has shown relatively low sensitivity for detecting four-repeat (4R) tau, which limits its utility in 4R tauopathies such as progressive supranuclear palsy (PSP). Previous studies have suggested that the first component of principal-component analysis includes non-disease-related uptake in non-Alzheimer tauopathies. In this study, we tested the hypothesis that subtracting this component could increase sensitivity to 4R tau using a large PSP cohort. Methods: Prospectively recruited patients with PSP (n = 141; 80 Richardson syndrome, 44 PSP-subcortical, and 17 PSP-cortical variants) and controls (n = 102) underwent [18F]flortaucipir PET. The first principal component (PC1) was extracted from the SUV ratio (SUVR) images of 62 controls and then subtracted from the remaining controls (n = 40) and all PSP patients. We compared the diagnostic performance before and after PC1 subtraction by evaluating SUVR differences between PSP and controls, as well as across PSP clinical variants, and by calculating correlation coefficients between SUVR and the severity of tau pathology. Results: Area under the receiver operating characteristic curves differentiating PSP and controls were improved by PC1 subtraction in the frontal white matter (0.54 to 0.67; P = 0.002) and subcortical (0.69 to 0.87; P < 0.001) regions. In the frontal regions, no differences were observed across PSP clinical variants before PC1 subtraction, whereas the PSP-cortical variant showed an SUVR higher than that of the PSP Richardson syndrome and PSP-subcortical variants after PC1 subtraction (adjusted P < 0.05). A correlation with the severity of tau pathology was observed only in the red nucleus before PC1 subtraction, whereas correlations were observed in the precentral, superior frontal gyrus, and red nucleus after PC1 subtraction (adjusted P < 0.05). Conclusion: Our approach enhanced the diagnostic performance of [18F]flortaucipir PET in PSP and increased sensitivity to 4R tau, suggesting that subtracting the first principal component improves the detectability of subtle 4R tau uptake and the potential utility of [18F]flortaucipir PET imaging for non-Alzheimer tauopathies.