Progressive Supranuclear Palsy Rating Scale Research Articles

Combined Assessment of Function and Survival to Demonstrate the Effect of Treatment on Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative disorder for which there are currently no disease-modifying treatments. Recent trials of potential therapies had durations of 12 months, which may be insufficient because of nonrandom missingness due to death. Longer durations, incorporating PSP Rating Scale and survival, can reduce the potential for type II error. Selecting efficacy measures more sensitive to disease modification may facilitate identification of treatment effect. The objective of this study was to evaluate the simulated phase 3 PSP trial assessing the effect of disease-modifying intervention on a novel combined primary endpoint comprising function (PSP Rating Scale) and survival, the Combined Assessment of Function and Survival (CAFS), and to determine operating characteristics of the CAFS. To simulate PSP progression in the trial population, we developed models of PSP Rating Scale and survival using data from published clinical studies. These models were used to define operating characteristics of the CAFS for use in a phase 3 trial. The sample size determined (N = 384; 1:1 randomization) would provide >80% power to detect significant treatment effects on the CAFS compared with placebo. The CAFS provides good operating characteristics and increased power to detect moderate treatment effects on the PSP Rating Scale. We propose a trial design allowing potential detection of treatment effects at a preplanned interim analysis after participants complete 12 months of treatment, with assessment of effects of treatment (≤24 months) on survival. Use of the CAFS could provide a comprehensive and robust estimate of the clinical benefit of future therapies. © 2024 UCB. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Efficiency of multivariate tests in trials in progressive supranuclear palsy

Measuring disease progression in clinical trials for testing novel treatments for multifaceted diseases as progressive supranuclear palsy (PSP), remains challenging. In this study we assess a range of statistical approaches to compare outcomes as measured by the items of the progressive supranuclear palsy rating scale (PSPRS). We consider several statistical approaches, including sum scores, a modified PSPRS rating scale that had been recommended by FDA in a pre-IND meeting, multivariate tests, and analysis approaches based on multiple comparisons of the individual items. In addition, we propose two novel approaches which measure disease status based on Item Response Theory models. We assess the performance of these tests under various scenarios in an extensive simulation study and illustrate their use with a re-analysis of the ABBV-8E12 clinical trial. Furthermore, we discuss the impact of the FDA-recommended scoring of item scores on the power of the statistical tests. We find that classical approaches as the PSPRS sum score demonstrate moderate to high power when treatment effects are consistent across the individual items. The tests based on Item Response Theory (IRT) models yield the highest power when the simulated data are generated from an IRT model. The multiple testing based approaches have a higher power in settings where the treatment effect is limited to certain domains or items. The study demonstrates that there is no one-size-fits-all testing procedure for evaluating treatment effects using PSPRS items; the optimal method varies based on the specific effect size patterns. The efficiency of the PSPRS sum score, while generally robust and straightforward to apply, varies depending on the specific patterns of effect sizes encountered and more powerful alternatives are available in specific settings. These findings can have important implications for the design of future clinical trials in PSP and similar multifaceted diseases.

Immunometabolic Signature and Tauopathy Markers in Blood Cells of Progressive Supranuclear Palsy.

Peripheral immune cells critically contribute to the clinical-pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard. Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort. Seventy-one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil-to-lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase 1 (HO-1) pathway and the total tau (t-tau) and phosphorylated tau (p-tau) proteins. Case-control comparison and correlation analyses were performed. PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO-1 pathway activated in patients. P-tau, but not t-tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS. PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO-1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p-tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society.

The contribution of white matter changes to clinical phenotype in progressive supranuclear palsy

White matter hyperintensities (WMH) are considered magnetic brain imaging (MRI) biomarkers of cerebral small vessel disease but their clinical role in neurodegenerative-related disorders is poorly understood. This study describes the distribution of WMH on brain MRI in Progressive Supranuclear Palsy (PSP) in comparison with Parkinson’s disease (PD) and explores their possible impact on disease’s features. Sixty PSP and 33 PD patients were included. Motor symptoms, cardiovascular risk factors and the age-related white matter changes (ARWMC) score was computed to rate WMH for both groups. Pearson’s correlation and linear or logistic regression analysis were used to check for relationships between ARWMC and PSP clinical scores. The mean (standard deviation) ARWMC total score in the PSP cohort was 4.66 (3.25). Any degree of WMH was present in 68% of PSP (ARWMC +). Compared to ARWMC-, ARWMC + did not have greater disease severity or more cardiovascular risk factors. WMH were frequently localized in fronto-parietal lobes and were mild in severity. Linear regression analysis showed that ARWMC total score was related to the PSP-rating scale, irrespective of age, disease duration and the Charlson modified comorbidity index. Logistic regression analysis confirmed that ARWMC total score was related to the use of wheelchair, irrespective of above-mentioned covariates. Vascular risk factors as well as severity and distribution of WMH did not have an impact on the PSP phenotype. No differences were found with PD patients. Our results suggest that WMH in PSP might be markers of neurodegenerative-related pathology rather than being simple expression of atherosclerotic cerebrovascular changes.

Quantitative Comparisons of Progressive Supranuclear Palsy Rating Scale Versions Using Item Response Theory.

Progressive supranuclear palsy (PSP) is a neurodegenerative, late-onset disease that is challenging in terms of assessment. The Progressive Supranuclear Palsy Rating Scale (PSPRS), a 28-item clinician-reported scale, is the most established clinical outcome assessment method. Recently, the U.S. Food and Drug Administration (FDA) has proposed a subscale of 10 items as an alternative to full PSPRS. To quantitatively evaluate and compare the properties of full PSPRS and the FDA subscale using item response theory. To develop a progression model of the disease and assess relative merits of study designs and analysis options. Data of 979 patients from four interventional trials and two registries were available for analysis. Our investigation was divided into: (1) estimating informativeness of the 28 items; (2) estimating disease progression; and (3) comparing the scales, trial designs, and analysis options with respect to power to detect a clinically relevant treatment effect. PSPRS item scores had a low pairwise correlation (r = 0.17 ± 0.14) and the items irritability, sleep difficulty, and postural tremor were uncorrelated with the other items. The FDA-selected items displayed higher correlation (r = 0.35 ± 0.14) and were the basis for a longitudinal item response model including disease progression. Trial simulations indicated that identification of a disease-modifying treatment effect required less than half the study size if the analysis was based on longitudinal item information compared with total scores at end-of-treatment. A longitudinal item response model based on the FDA-selected PSPRS items is a promising tool in evaluating treatments for PSP. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

CSF Proteomics in Patients With Progressive Supranuclear Palsy.

Identification of fluid biomarkers for progressive supranuclear palsy (PSP) is critical to enhance therapeutic development. We implemented unbiased DNA aptamer (SOMAmer) proteomics to identify novel CSF PSP biomarkers. This is a cross-sectional study in original (18 clinically diagnosed PSP-Richardson syndrome [PSP-RS], 28 cognitively healthy controls]), validation (23 PSP-RS, 26 healthy controls), and neuropathology-confirmed (21 PSP, 52 non-PSP frontotemporal lobar degeneration) cohorts. Participants were recruited through the University of California, San Francisco, and the 4-Repeat Neuroimaging Initiative. The original and neuropathology cohorts were analyzed with the SomaScan platform version 3.0 (5026-plex) and the validation cohort with version 4.1 (7595-plex). Clinical severity was measured with the PSP Rating Scale (PSPRS). CSF proteomic data were analyzed to identify differentially expressed targets, implicated biological pathways using enrichment and weighted consensus gene coexpression analyses, diagnostic value of top targets with receiver-operating characteristic curves, and associations with disease severity with linear regressions. A total of 136 participants were included (median age 70.6 ± 8 years, 68 [50%] women). One hundred fifty-five of 5,026 (3.1%), 959 of 7,595 (12.6%), and 321 of 5,026 (6.3%) SOMAmers were differentially expressed in PSP compared with controls in original, validation, and neuropathology-confirmed cohorts, with most of the SOMAmers showing reduced signal (83.1%, 95.1%, and 73.2%, respectively). Three coexpression modules were associated with PSP across cohorts: (1) synaptic function/JAK-STAT (β = -0.044, corrected p = 0.002), (2) vesicle cytoskeletal trafficking (β = 0.039, p = 0.007), and (3) cytokine-cytokine receptor interaction (β = -0.032, p = 0.035) pathways. Axon guidance was the top dysregulated pathway in PSP in original (strength = 1.71, p < 0.001), validation (strength = 0.84, p < 0.001), and neuropathology-confirmed (strength = 0.78, p < 0.001) cohorts. A panel of axon guidance pathway proteins discriminated between PSP and controls in original (area under the curve [AUC] = 0.924), validation (AUC = 0.815), and neuropathology-confirmed (AUC = 0.932) cohorts. Two inflammatory proteins, galectin-10 and cytotoxic T lymphocyte-associated protein-4, correlated with PSPRS scores across cohorts. Axon guidance pathway proteins and several other molecular pathways are downregulated in PSP, compared with controls. Proteins in these pathways may be useful targets for biomarker or therapeutic development.

A Short Progressive Supranuclear Palsy Quality of Life Scale.

The Progressive Supranuclear Palsy quality of life scale (PSP-QoL) has been shown to be a useful tool for capturing health-related quality of life of patients in "everyday life" and in progressive supranuclear palsy (PSP) research. However, at 45 items in length, the questionnaire can take a long time, exhausting PSP patients, in particular if cognitive impaired, which can have a negative impact on the assessment. The aim of this study was to establish a condensed version of the PSP-QoL for research and routine clinical care. In this retrospective study, data originating from a German cohort of PSP patients was analyzed. Data from 245 PSP patients were included in this study. The short PSP-QoL questionnaire was created using a two-factor solution and item-total and inter-item correlations for mental and physical aspects of daily living of the PSP-QoL followed by confirmatory factor analysis. The final scale included 12 items representing mental (five items) and physical symptoms (seven items). The specified two-factor model displayed an excellent fit in the confirmatory factor analysis. The short Progressive Supranuclear Palsy Quality of Life scale (PSP-ShoQoL) correlated moderately with the PSP Rating Scale (r [243] = 0.514, P < 0.001) and Geriatric depression scale (r [231] = 0.548, P < 0.001). Sensitivity to change confirmed a significant decrease in QoL after 12 months. In this study, we created a 12-item PSP-ShoQoL designed to "facilitate" daily clinical work that correlated strongly with the PSP-QoL and was sensitive to change. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

AYURVEDIC MANAGEMENT OF PROGRESSIVE SUPRANUCLEAR PALSY (PSP): A CASE REPORT

Progressive Supranuclear Palsy (PSP) is a rare neurological condition that can cause problems with balance, movement, vision, speech and swallowing. This condition could be clinically compared to Kaphavrita Vyana Vata and Asthi-Majja gata Vata in Ayurveda based on signs and symptoms. A 73-year-old male patient visited the Geriatric OPD of Panchakarma Department, Government Ayurveda College Panchakarma Hospital, Poojappura, Thiruvananthapuram, Kerala, India, with complaints of balance and mobility problems, including frequent falls, changes in behaviour like irritability, inability to control eye and upward eyelid movements along with slowness of thought and some memory problems. The patient was advised for IP admission. He was diagnosed with Progressive Supranuclear Palsy (PSP) from MRI-Brain. From an Ayurvedic perspective, this condition could be considered Kaphavrita Vyana Vata and Asthi-Majja gata Vata based on signs and symptoms. Considering all the factors, the treatment principles of Avarana Vata and Asthi-Majja gata Vata were followed in this case. The assessment criteria were based on the Progressive Supranuclear Palsy Rating Scale (PSPRS) and the WHO Quality of Life Scale (WHOQOLS). The case report shows that Ayurvedic treatment effectively reduces the signs and symptoms of Progressive Supranuclear Palsy (PSP) in the early stage. No adverse effect was found during the treatment. The assessment of the disease by the Progressive Supranuclear Palsy Rating Scale (PSPRS) showed improvement by changing the total score from 20 to 9 before and after treatment. The assessment with the World Health Organisation Quality of Life Scale (WHOQOLS) showed that the patient's quality of life improved from 45% to 64.6% before and after treatment.

Longitudinal change of energy expenditure, body composition and dietary habits in Progressive Supranuclear Palsy patients.

Alterations in metabolic status, body composition, and food intake are present in all neurodegenerative diseases. Aim of this study was to detect the progression of these changes in Progressive Supranuclear Palsy (PSP). We conducted a longitudinal study of 15 patients with PSP. The assessments were performed at baseline (T0) and after 7(IQR = 5) months of follow-up (T1). We collected anthropometric measures including body weight, height, body mass index and waist circumference, metabolic parameters through indirect calorimeters, body composition using bioimpedance analysis, and dietary habits with a validated questionnaire. PSP-rating scale (PSP-rs) was used to evaluate disease severity and dysphagia. The majority of patients (66.66%) presented PSP-Richardson Syndrome and 33.33% the other variant syndromes of the disease. At T1 there was a decrease in intake of total daily calories (p < 0.001), proteins (p < 0.001), fibers (p = 0.001), calcium (p = 0.008), iron (p < 0.001), zinc (0.034), vitamin E (p = 0.006) and folates (p = 0.038) compared to T0. No other changes were found. As for T1 data, no significant differences were shown according to disease phenotypes or the presence of clinically significant dysphagia for solids. Within a mid-term follow up, PSP patients presented reduced caloric and proteins intake regardless the presence of dysphagia. The PSP-rs is likely not adequate to assess dysphagia, which should be investigated by specific clinical scales or instrumental examinations. With the goal of maintaining adequate nutritional status, the administration of protein and vitamin supplements should be considered even in the absence of dysphagia evidenced by the rating scales.

Clinical Utility of Tectal Plate Measurements on Magnetic Resonance Imaging in Progressive Supranuclear Palsy.

Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), observed in PSP-Richardson's syndrome (PSP-RS) and to a lesser extent PSP-parkinsonism (PSP-P). Our aim was to critically evaluate the utility of manual magnetic resonance imaging measurements of the midbrain tectal plate as a diagnostic biomarker in PSP. Length of the tectal plate and width of the superior and inferior colliculi were measured in 40 PSP (20 PSP-RS and 20 PSP-P) patients and compared with 20 Parkinson's disease and 20 healthy control subjects. Tectal plate length was reduced in both PSP groups compared with Parkinson's disease and control subjects and was most abnormal in PSP-RS followed by PSP-P. Reduced tectal plate length was associated with worse PSP Rating Scale scores. Simple manual measurements of tectal plate length show utility as a diagnostic biomarker in PSP, particularly for PSP-RS.

Striatal and Extrastriatal Monoaminergic Disruption in Progressive Supranuclear Palsy.

As a biomarker targeting vesicular monoamine transporter 2 (VMAT2), 18F-9-fluoropropyldihydrotetrabenazine (18F-FP-DTBZ) positron emission tomography (PET) is highly accurate in diagnosing Parkinson's disease (PD) and assessing its severity. However, evidence is insufficient in patients with progressive supranuclear palsy (PSP). We evaluated the striatal and extrastriatal monoaminergic disruption of PSP and differences in patterns between patients with PSP, PD, and healthy controls (HCs) using 18F-FP-DTBZ PET, as well as its correlations with the clinical characteristics of PSP. We recruited 58 patients with PSP, 23 age- and duration-matched patients with PD, as well as 17 HCs. Patients were scanned using 18F-FP-DTBZ PET/computed tomography, and images were spatially normalized and analyzed based on the volume of interest. VMAT2 binding differed significantly in the striatum and substantia nigra among the groups (P < 0.001). A more severe disruption in the caudate was noted in the PSP group (P < 0.001) than in the PD group. However, no differences were found in the nucleus accumbens, hippocampus, amygdala, or raphe between the PD and PSP groups. Within the PSP group, striatal VMAT2 binding was significantly associated with the fall/postural stability subscore of the PSP Rating Scale, especially in the putamen. Furthermore, VMAT2 binding was correlated with Mini-Mental State Examination or Montreal Cognitive Assessment in the hippocampus. Caudate disruptions showed prominent differences among the groups. VAMT2 binding in the striatum and hippocampus reflects the severity of fall/postural stability and cognition, respectively. © 2024 International Parkinson and Movement Disorder Society.

Dominance of Tau Burden in Cortical Over Subcortical Regions Mediates Glymphatic Activity and Clinical Severity in PSP.

Progressive supranuclear palsy (PSP) is a tauopathy that involves subcortical regions but also extends to cortical areas. The clinical impact of different tau protein sites and their influence on glymphatic dysfunction have not been investigated. Participants (n = 55; 65.6 ± 7.1 years; 29 women) with PSP (n = 32) and age-matched normal controls (NCs; n = 23) underwent 18 F-Florzolotau tau PET, MRI, PSP Rating Scale (PSPRS), and Mini-Mental State Examination. Cerebellar gray matter (GM) and parametric estimation of reference signal intensity were used as references for tau burden measured by SUV ratios. Glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS). Parametric estimation of reference signal intensity is a better reference than cerebellar GM to distinguish tau burden between PSP and NCs. PSP patients showed higher cortical and subcortical tau SUV ratios than NCs ( P < 0.001 and <0.001). Cortical and subcortical tau deposition correlated with PSPRS, UPDRS, and Mini-Mental State Examination scores (all P 's < 0.05). Cortical tau deposition was further associated with the DTI-ALPS index and frontal-temporal-parietal GM atrophy. The DTI-ALPS indexes showed a significantly negative correlation with the PSPRS total scores ( P < 0.01). Finally, parietal and occipital lobe tau depositions showed mediating effects between the DTI-ALPS index and PSPRS score. Cortical tau deposition is associated with glymphatic dysfunction and plays a role in mediating glymphatic dysfunction and clinical severity. Our results provide a possible explanation for the worsening of clinical severity in patients with PSP.

Predicting Disability in Progressive Supranuclear Palsy Using Bedside Frontal-Lobe Signs.

Frontal lobe signs in progressive supranuclear palsy (PSP) are prevalent and occur early in the disease. Although they are recognized in clinical practice, studies are needed to systematically investigate them for an in-depth understanding of the neurological substrate and their potential prognostic implications in the disease. To study the predictive role of frontal lobe signs in PSP, as well as to describe their neuropsychological and anatomical correlations. Nine recognized signs of frontal lobe dysfunction were assessed in 61 patients with PSP. Those signs able to predict PSP Rating Scale (PSPRS) score at baseline were selected, a survival analysis was performed and associations with neuropsychological tests and cortical thickness parameters in brain MRI were studied. Grasping, anosognosia and orobuccal apraxia predicted the PSPRS score independently of age, gender, clinical subtype and disease duration. The occurrence of groping in the first 4 years could be a predictor of survival. Grasping and anosognosia were associated with frontal cognitive dysfunction, whereas orobuccal apraxia and groping were related to a more widespread cognitive impairment, involving temporal-parietal areas. Presence of groping showed an extensive cortical atrophy, with predominant prefrontal, temporal and superior parietal cortical thinning. Grasping, groping, anosognosia and orobuccal apraxia are easily evaluable bedside clinical signs that reflect distinct stages of disease progression. Grasping, anosognosia and orobuccal apraxia predict disease disability in patients with PSP, and early onset groping could be a survival predictor.

Association of Neurofilament Light Chain, [18F]PI-2620 Tau-PET, TSPO-PET, and Clinical Progression in Patients With β-Amyloid-Negative CBS.

Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in β-amyloid (Aβ)-negative CBS. We included patients with clinically diagnosed Aβ-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [18F]PI-2620-PET for assessing tau pathology, [18F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction). Overall, 21 patients with Aβ-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [18F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model. [18F]PI-2620 tau-PET, [18F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aβ-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.

The impact of neuropsychiatric symptoms in in PSP. An overview of quality of life and functionality

AbstractBackgroundProgressive supranuclear paralysis (PSP) is an atypical parkinsonian disorder associated with oculomotor features, motor disturbances, postural instability along with cognitive problems and neuropsychiatric symptoms. Functional impairment and quality of life (QOL) are often related to the motor symptoms. Our aim was to investigate the contribution of neuropsychiatric symptoms such as depression, anxiety and sleep disturbance to functionality and QOL.MethodWe used data from 69 patients meeting criteria for probable PSP from the Rossy PSP Centre. Neuropsychiatric symptoms, severity and functionality were examined using validated rating scales including the Hamilton Anxiety Rating Scale (HAM‐A) for anxiety, Geriatric Depression Scale (GDS) for depression, Epworth sleepiness scale (ESS) for sleep and Neuropsychiatry Inventory (NPI) total scores. To examine function, we used the Schwab and England Activities of Daily Living Scale (SEADL), severity of disease we used PSP rating scale and for QOL the (EQ‐5D‐5L). Cognition was examined using the Montreal Cognitive Assessment (MOCA). We investigated the relationships between neuropsychiatric symptoms and function and QOL using Pearson correlations controlling for multiple comparisons with false discovery test.ResultIn our sample (37.7% female, mean age 71.2+/‐ 6.5) 26.9% had depression, 13% had anxiety, 97.3% had scores compatible with cognitive impairment. Mean QOL‐EQ‐5D‐5L score was 50.4 +/‐ 25.3, mean PSP‐RS 39.5 +/‐ 12.7. Subgroups were made for QOL and functionality analysis. We found negative correlations between SEADL and HAM‐A (r ‐0.32 p = 0.01), and GDS (r ‐0.32 p = 0.01); between QOL‐EQ‐5D‐5L and GDS (r‐0.51 p = 0.014) and HAM‐A (r‐0.49 p = 0.014). Positive correlations were found between SEADL and QOL‐EQ‐5D‐5L (r = 0.61 p = 0.005) and between PSP‐RS and ESS (r 0.35 p = 0.004). The SEADL and PSP‐RS were negatively correlated (r‐0.39 p = 0.002).ConclusionConsistent with apriori hypotheses we found anxiety, depression and PSP‐RS are related to function as measured by the SEADL and quality of life of PSP patients. Sleep disturbance was related to PSP‐RS. These results emphasize the importance of comprehensive evaluations to better capture the multi‐faceted impairments seen in PSP that have a meaningful impact on the patient’s life.

The contribution of Oculomotor and Motor Deficits in The Assessment of Executive Function in Progressive Supranuclear Palsy Patients

AbstractBackgroundProgressive supranuclear palsy (PSP) was first described in 1964 and is associated with motor, oculomotor, and cognitive deficits. Cognitive assessments often assume intact physical function. Some tests like The Trail Making Test (TMT), a measure of executive function may be impacted by oculomotor and motor impairments. Our aim was to investigate the impact of oculomotor impairments and arm dysfunction on the TMT.Method71 patients from the Rossy PSP Center that met criteria for probable PSP and underwent a neuropsychological test battery, the Toronto Cognitive Assessment (TorCA), were included. Data from the following tests and assessments were used for this study: TMT A and B time, digit forwards and backwards, verbal and animal fluency, Benson copy, and Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) delayed recall, PSP Rating Scale (PSPRS) total score and its oculomotor subscore, MDS‐Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS part III) subscore of the dominant hand was used to rate the motor impairment. We performed spearman correlations and used false discovery rate test correction for multiple comparisons.ResultThe PSP patients (60.6% male, mean age 71.3+/‐6.61) had mean PSPRS score of 41.5+/‐15, PSPRS‐oculomotor subscore 8.0+/‐3, and MDS‐UPDRS III subscore dominant hand 6.5+/‐3.3. We found a positive correlation between PSPRS‐oculomotor subscore and TMT A (r = 0.43 p = 0.005) and TMT B (r = 0.35 p = 0.008). We also found negative correlations between PSPRS‐oculomotor subscore and digits backward (r = ‐0.39 p = 0.005), Benson copy (r = ‐0.39 p = 0.005), CERAD delayed recall (r = ‐0.29 p = 0.034), and animal fluency (r = ‐0.44 p = 0.004). No tests were related to MDS‐UPDRS part III subscore of the dominant hand.ConclusionOculomotor but not motor function affect TMT A and B. However, oculomotor function also relates to other executive and non‐executive tests that do not require visual scanning. Although important to factor in physical deficits when doing cognitive assessments, the TMT appears to be a reliable test for assessing cognitive function in patients with PSP who can perform the test.

Accurate digital quantification of tau pathology in progressive supranuclear palsy

The development of novel treatments for Progressive Supranuclear Palsy (PSP) is hindered by a knowledge gap of the impact of neurodegenerative neuropathology on brain structure and function. The current standard practice for measuring postmortem tau histology is semi-quantitative assessment, which is prone to inter-rater variability, time-consuming and difficult to scale. We developed and optimized a tau aggregate type-specific quantification pipeline for cortical and subcortical regions, in human brain donors with PSP. We quantified 4 tau objects (‘neurofibrillary tangles’, ‘coiled bodies’, ‘tufted astrocytes’, and ‘tau fragments’) using a probabilistic random forest machine learning classifier. The tau pipeline achieved high classification performance (F1-score > 0.90), comparable to neuropathologist inter-rater reliability in the held-out test set. Using 240 AT8 slides from 32 postmortem brains, the tau burden was correlated against the PSP pathology staging scheme using Spearman’s rank correlation. We assessed whether clinical severity (PSP rating scale, PSPRS) score reflects neuropathological severity inferred from PSP stage and tau burden using Bayesian linear mixed regression. Tufted astrocyte density in cortical regions and coiled body density in subcortical regions showed the highest correlation to PSP stage (r = 0.62 and r = 0.38, respectively). Using traditional manual staging, only PSP patients in stage 6, not earlier stages, had significantly higher clinical severity than stage 2. Cortical tau density and neurofibrillary tangle density in subcortical regions correlated with clinical severity. Overall, our data indicate the potential for highly accurate digital tau aggregate type-specific quantification for neurodegenerative tauopathies; and the importance of studying tau aggregate type-specific burden in different brain regions as opposed to overall tau, to gain insights into the pathogenesis and progression of tauopathies.

6 Remote Smartphone Cognitive and Motor Testing in Frontotemporal Dementia Research: Feasibility, Reliability, and Validity

Objective:Therapeutics targeting frontotemporal dementia (FTD) are entering clinical trials. There are challenges to conducting these studies, including the relative rarity of the disease. Remote assessment tools could increase access to clinical research and pave the way for decentralized clinical trials. We developed the ALLFTD Mobile App, a smartphone application that includes assessments of cognition, speech/language, and motor functioning. The objectives were to determine the feasibility and acceptability of collecting remote smartphone data in a multicenter FTD research study and evaluate the reliability and validity of the smartphone cognitive and motor measures.Participants and Methods:A diagnostically mixed sample of 207 participants with FTD or from familial FTD kindreds (CDR®+NACC-FTLD=0 [n=91]; CDR®+NACC-FTLD=0.5 [n=39]; CDR®+NACC-FTLD&gt;1 [n=39]; unknown [n=38]) were asked to remotely complete a battery of tests on their smartphones three times over two weeks. Measures included five executive functioning (EF) tests, an adaptive memory test, and participant experience surveys. A subset completed smartphone tests of balance at home (n=31) and a finger tapping test (FTT) in the clinic (n=11). We analyzed adherence (percentage of available measures that were completed) and user experience. We evaluated Spearman-Brown split-half reliability (100 iterations) using the first available assessment for each participant. We assessed test-retest reliability across all available assessments by estimating intraclass correlation coefficients (ICC). To investigate construct validity, we fit regression models testing the association of the smartphone measures with gold-standard neuropsychological outcomes (UDS3-EF composite [Staffaroni et al., 2021], CVLT3-Brief Form [CVLT3-BF] Immediate Recall, mechanical FTT), measures of disease severity (CDR®+NACC-FTLD Box Score &amp; Progressive Supranuclear Palsy Rating Scale [PSPRS]), and regional gray matter volumes (cognitive tests only).Results:Participants completed 70% of tasks. Most reported that the instructions were understandable (93%), considered the time commitment acceptable (97%), and were willing to complete additional assessments (98%). Split-half reliability was excellent for the executive functioning (r’s=0.93-0.99) and good for the memory test (r=0.78). Test-retest reliabilities ranged from acceptable to excellent for cognitive tasks (ICC: 0.70-0.96) and were excellent for the balance (ICC=0.97) and good for FTT (ICC=0.89). Smartphone EF measures were strongly associated with the UDS3-EF composite (ß's=0.6-0.8, all p&lt;.001), and the memory test was strongly correlated with total immediate recall on the CVLT3-BF (ß=0.7, p&lt;.001). Smartphone FTT was associated with mechanical FTT (ß=0.9, p=.02), and greater acceleration on the balance test was associated with more motor features (ß=0.6, p=0.02). Worse performance on all cognitive tests was associated with greater disease severity (ß's=0.5-0.7, all p&lt;.001). Poorer performance on the smartphone EF tasks was associated with smaller frontoparietal/subcortical volume (ß's=0.4-0.6, all p&lt;.015) and worse memory scores with smaller hippocampal volume (ß=0.5, p&lt;.001).Conclusions:These results suggest remote digital data collection of cognitive and motor functioning in FTD research is feasible and acceptable. These findings also support the reliability and validity of unsupervised ALLFTD Mobile App cognitive tests and provide preliminary support for the motor measures, although further study in larger samples is required.

Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women

Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, pooling patient data irrespective of sex concluded no efficacy. Here, analyzing sex-dependency in a 52 week-long- PSP clinical trial (involving over 200 patients) demonstrated clear baseline differences in brain ventricular volumes, a secondary endpoint. Dramatic baseline ventricular volume-dependent/volume increase correlations were observed in 52-week-placebo-treated females (r = 0.74, P = 2.36–9), whereas davunetide-treated females (like males) revealed no such effects. Assessment of primary endpoints, by the PSP Rating Scale (PSPRS) and markedly more so by the Schwab and England Activities of Daily Living (SEADL) scale, showed significantly faster deterioration in females, starting at trial week 13 (P = 0.01, and correlating with most other endpoints by week 52). Twice daily davunetide treatments slowed female disease progression and revealed significant protection according to the SEADL scale as early as at 39 weeks (P = 0.008), as well as protection of the bulbar and limb motor domains considered by the PSPRS, including speaking and swallowing difficulties caused by brain damage, and deterioration of fine motor skills, respectably (P = 0.01), at 52 weeks. Furthermore, at 52 weeks of trial, the exploratory Geriatric Depression Scale (GDS) significantly correlated with the SEADL scale deterioration in the female placebo group and demonstrated davunetide-mediated protection of females. Female-specific davunetide-mediated protection of ventricular volume corresponded to clinical efficacy. Together with the significantly slower disease progression seen in men, the results reveal sex-based drug efficacy differences, demonstrating the neuroprotective and disease-modifying impact of davunetide treatment for female PSP patients.

A - 9 The Progressive Supranuclear Palsy Rating Scale Identifies Early Motor Symptoms in Primary Progressive Aphasia.

This study examined cross-sectional differences in Progressive Supranuclear Palsy Rating Scale (PSPRS) scores among participants with behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA). We hypothesized that participants with nonfluent/agrammatic PPA (nfPPA) will show the highest (worst) PSPRS scores and greater gray matter atrophy in regions associated with progressive supranuclear palsy (PSP) pathology. Participants were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium (ALLFTD). Analyses were limited to first visit data. Ten anatomic regions of interest were pre-selected for analysis based on previously identified neuroanatomic correlates of PSPRS performance. Differences in participant characteristics and clinical outcomes were compared using pairwise comparison of means. Linear multivariable regression adjusting for age and total intracranial volume was used to examine associations between regional gray matter volumes and diagnosis. The analyses were stratified by disease severity. Participants with early-stage nfPPA had higher total PSPRS scores compared to those with bvFTD or semantic dementia (SD) and performed more poorly on domains of dysphagia, fine motor movements, falls, postural stability, dysarthria, saccadic eye movements, and motor rigidity. Participants with advanced-stage nfPPA showed greater atrophy in the left putamen, supplementary motor area, and precentral gyrus than those with bvFTD. Our study highlights the phenotypic complexity of PPA and the utility of the PSPRS in capturing early motor symptoms in nfPPA. These data suggest that the PSPRS may facilitate early intervention in identifying and facilitating treatment of early motor symptoms, decreasing disability and improving quality of life in PPA.