Progressive Supranuclear Palsy Rating Scale Research Articles

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. © 2024 International Parkinson and Movement Disorder Society.

Striatal and Extrastriatal Monoaminergic Disruption in Progressive Supranuclear Palsy.

As a biomarker targeting vesicular monoamine transporter 2 (VMAT2), 18 F-9-fluoropropyldihydrotetrabenazine (18 F-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 18 F-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 18 F-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.

Utilizing speech analysis to differentiate progressive supranuclear palsy from Parkinson's disease

IntroductionDistinguishing Parkinson's disease (PD) from Progressive supranuclear palsy (PSP) at early disease stages is important for clinical trial enrollment and clinical care/prognostication. MethodsWe recruited 21 participants with PSP(n = 11) or PD(n = 10) with reliable caregivers. Standardized passage reading, counting, and sustained phonation were recorded on the BioDigit Home tablet (BioSensics LLC, Newton, MA USA), and speech features from the assessments were analyzed using the BioDigit Speech platform (BioSensics LLC, Newton, MA USA). An independent t-test was performed to compare each speech feature between PSP and PD participants. We also performed Spearman's correlations to evaluate associations between speech measures and clinical scores (e.g., PSP rating scales and MoCA). In addition, the model's performance in classifying PSP and PD was evaluated using Rainbow passage reading analysis. ResultsDuring Rainbow passage reading, PSP participants had a significantly slower articulation rate (2.45(0.49) vs 3.60(0.47) words/minute), lower speech-to-pause ratio (2.33(1.08) vs 3.67(1.18)), intelligibility dynamic time warping (DTW, 0.26(0.19) vs 0.53(0.26)), and similarity DTW (0.43(0.27) vs 0.67(0.13)) compared to PD participants. PSP participants also had longer pause times (17.24(5.47) vs 8.45(3.13) sec) and longer total signal times (52.44(6.67) vs (36.67(6.73) sec) when reading the passage. In terms of the phonation ‘a’, PSP participants showed a significant higher spectral entropy, spectral centroid, and spectral spread compared to PD participants and no differences were found for phonation ‘e’. PD participants had more accurate reverse number counts than PSP participants (14.89(3.86) vs 7.36(4.67)). PSP Rating Scale (PSPRS) dysarthria (r = 0.79, p = 0.004) and bulbar item scores (r = 0.803, p = 0.005) were positively correlated with articulation rate in reverse number counts. Correct reverse number counts were positively correlated with total Montreal Cognitive Assessment scores (r = 0.703, p = 0.016). Machine learning models using passage reading-derived measures obtained an AUC of 0.93, and the sensitivity/specificity in correctly classifying PSP and PD participants were 0.95 and 0.90, respectively. ConclusionOur study demonstrates the feasibility of differentiating PSP from PD using a digital health technology platform. Further multi-center studies are needed to expand and validate our initial findings.

Longitudinal study of Progressive Supranuclear Palsy (PSP) using remote at-home multi-modal digital assessments and wearable devices (S51.002)

<h3>Objective:</h3> To measure Progressive Supranuclear Palsy (PSP) progression remotely in participants’ homes using wearable sensors, digital speech and cognitive assessments. <h3>Background:</h3> There are limited studies using technology to objectively measure disease progression in PSP and no studies using wearable technology in participants’ homes. We hypothesized that remote, objective, quantitative measures of disease progression will facilitate clinical trials and help spur development of new therapies for PSP. <h3>Design/Methods:</h3> Patients with clinically probable PSP by MDS 2017 criteria able to ambulate ≥10 feet unassisted were recruited at Massachusetts General Hospital and Johns Hopkins from November 2021 through September, 2022 and followed virtually monthly for 1 year. Motor assessments performed monthly wearing LEGSys™ and BalanSense™ (BioSensics LLC, Newton, MA USA) devices included: balance assessments, 5x sit-to-stand, 3-meter timed up and go, and 2-minute walk tests. Participants wore PAMSys™ (BioSensics LLC) pendant sensors for 1 year to measure physical activity, walking parameters, postural transitions, and falls during daily activities. Digital cognitive and speech assessments performed using the BioDigit Home™ (BioSensics LLC) tablet every 3 months included: Color Trails, Conflicting Instructions, Go/No-Go, Forward and Backward Digit Span. The PSP Rating Scale (PSPRS), MoCA, PSP-QoL and CBFS were collected virtually every 3 months or in-person. <h3>Results:</h3> As of October 2022, 11 PSP participants were enrolled. By April 2023, 7 participants will have completed 12 months of follow-up. One participant was unable to complete virtual assessments due to lack of caregiver support and 3 participants could not perform walking tasks after 6 months. Walking parameters, postural duration and transition times correlated strongly with disease progression as measured using the PSPRS and PSP-QoL. Instrumented gait measures correlated with activity levels. <h3>Conclusions:</h3> Our study demonstrates the feasibility of remote longitudinal measurement of PSP progression in participants’ homes using wearable devices and digital assessments. The study identifies possible digital biomarkers of PSP progression. <b>Disclosure:</b> Miss Sharma has nothing to disclose. Ms. Hall has received research support from National Institutes of Health. Miss Cole has nothing to disclose. Mr. Casado has received personal compensation for serving as an employee of BioSensics LLC. Dr. Mishra has received personal compensation for serving as an employee of Biosensics. Dr. Vaziri has received personal compensation for serving as an employee of Biosensics. Dr. Pantelyat has received personal compensation for serving as an employee of MedRhythms, Inc.. Dr. Pantelyat has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MedRhythms, Inc.. Dr. Pantelyat has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Kelly &amp; Ignoffo Law Group. The institution of Dr. Pantelyat has received research support from NIH/NIA. Dr. Wills has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Accordant, a CVS/Caremark company. Dr. Wills has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi/Genzyme. The institution of Dr. Wills has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono Pharmaceuticals. The institution of Dr. Wills has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx. Dr. Wills has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Parkinson’s Foundation. The institution of Dr. Wills has received research support from Parkinson’s Foundation. The institution of Dr. Wills has received research support from Biogen. The institution of Dr. Wills has received research support from Roche/Genentech. The institution of Dr. Wills has received research support from BioSensics.

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

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

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

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

Longitudinal clinical decline and baseline predictors in progressive supranuclear palsy

IntroductionProgressive supranuclear palsy (PSP) is associated with several clinical variants defined based on ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction, although little is known about how these features progress over time. We aimed to assess the evolution of these core clinical features across variants and assess baseline clinical and neuroimaging predictors of progression. MethodsNinety-three PSP patients were recruited by the Neurodegenerative Research Group, Mayo Clinic, and underwent two visits 1-year apart, with baseline MRI and [18F]flortaucipir PET. We compared baseline and annualized rates of clinical change on the PSP Rating Scale (total, ocular motor, gait/midline scores) and Montreal Cognitive Assessment, across PSP-Richardson's, PSP-Cortical and PSP-Subcortical variants and assessed relationships between rates of change and baseline regional imaging. ResultsOcular motor scores differed across groups at baseline and follow-up, with lowest scores observed in PSP-subcortical, but no differences were observed in rate of change across groups. PSP Rating Scale total and gait/midline scores differed across groups at follow-up and in rates of change, with PSP-subcortical showing the least impairment and slowest progression. Greatest cognitive impairment was observed in PSP-Cortical. Sample size estimates for treatment trials differed across PSP variants. Greater baseline flortaucipir uptake, but not volume, of midbrain and motor cortex correlated with faster rates of clinical decline. ConclusionThe PSP Rating Scale and its subscores might be useful markers for the prognostic stratification of PSP variants. Flortaucipir imaging at baseline may help predict rate of decline.

Symptomatology in 4-repeat tauopathies is associated with data-driven topology of [18F]-PI-2620 tau-PET signal

In recent years in vivo visualization of tau deposits has become possible with various PET radiotracers. The tau tracer [18F]PI-2620 proved high affinity both to 3-repeat/4-repeat tau in Alzheimer’s disease as well as to 4-repeat tau in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). However, to be clinically relevant, biomarkers should not only correlate with pathological changes but also with disease stage and progression. Therefore, we aimed to investigate the correlation between topology of [18F]PI-2620 uptake and symptomatology in 4-repeat tauopathies.72 patients with possible or probable 4-repeat tauopathy, i.e. 31 patients with PSP-Richardson’s syndrome (PSP-RS), 30 with amyloid-negative CBS and 11 with PSP-non-RS/CBS, underwent [18F]PI-2620-PET. Principal component analysis was performed to identify groups of similar brain regions based on 20–40 min p.i. regional standardized uptake value ratio z-scores. Correlations between component scores and the items of the PSP Rating Scale were explored.Motor signs like gait, arising from chair and postural instability showed a positive correlation with tracer uptake in mesial frontoparietal lobes and the medial superior frontal gyrus and adjacent anterior cingulate cortex. While the signs disorientation and bradyphrenia showed a positive correlation with tracer uptake in the parietooccipital junction, the signs disorientation and arising from chair were negatively correlated with tau-PET signal in the caudate nucleus and thalamus. Total PSP Rating Scale Score showed a trend towards a positive correlation with mesial frontoparietal lobes and a negative correlation with caudate nucleus and thalamus. While in CBS patients, the main finding was a negative correlation of tracer binding in the caudate nucleus and thalamus and a positive correlation of tracer binding in medial frontal cortex with gait and motor signs, in PSP-RS patients various correlations of clinical signs with tracer binding in specific cerebral regions could be detected.Our data reveal [18F]PI-2620 tau-PET topology to correlate with symptomatology in 4-repeat tauopathies. Longitudinal studies will be needed to address whether a deterioration of signs and symptoms over time can be monitored by [18F]PI-2620 in 4-repeat tauopathies and whether [18F]PI-2620 may serve as a marker of disease progression in future therapeutic trials. The detected negative correlation of tracer binding in the caudate nucleus and thalamus with the signs disorientation and arising from chair may be due to an increasing atrophy in these regions leading to partial volume effects and a relative decrease of tracer uptake in the disease course. As cerebral regions correlating with symptomatology differ depending on the clinical phenotype, a precise knowledge of clinical signs and symptoms is necessary when interpreting [18F]PI-2620 PET results.

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

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

ALLFTD Mobile App Balance and Finger Tapping Tasks: Task Description and Initial Reliability and Validity Findings

AbstractBackgroundMotor disturbances are common in patients with a variety of neurodegenerative and neurological syndromes, such as Parkinson’s disease and Frontotemporal Dementia (FTD). Accurately quantifying motoric changes could enable earlier detection and monitoring of these syndromes, and remote quantification may allow for more frequent assessments and may improve access to research for underrepresented and geographically dispersed participants. With these benefits in mind, investigators from the ALLFTD consortium developed smartphone tests of balance and finger tapping speed. Here we present preliminary test‐retest reliability and associations with gold standard tests.MethodThe tasks were analyzed in two independent samples. The first was an in‐person cohort of healthy older adults (n = 7), mild cognitive impairment (MCI, n = 1) and FTD (n = 3) who completed the smartphone standing/balance and finger tapping tests (FTT) twice in person. The second sample included 31 ALLFTD participants with a range of clinical presentations (healthy older adults [n = 11], FTD [n = 5], MCI [n = 2], unknown [n = 13]) who were asked to complete the balance test three times over two weeks at home. The primary outcomes were total taps for the FTT and root mean squared acceleration for the balance test. Test‐retest reliability was calculated using an intraclass correlation coefficient (ICC); given the small sample size, outliers (n = 6) were removed from the balance test. We tested the association of smartphone FTT with the gold standard mechanical FTT and the balance task with the CDR®+NACC‐FTLD‐SB (disease severity) using Spearman’s correlations. A Wilcoxon‐sign rank test compared participants with motor features on the Progressive Supranuclear Palsy Rating Scale (PSPRS&gt;0) to those without (PSPRS = 0).ResultThe smartphone FTT showed good test‐retest reliability (ICC = 0.78) and a strong correlation (r = 0.8,p&lt;0.05) with mechanical FTT. The test‐retest reliability for the balance task was excellent for the remote sample (ICC = 0.97) and in‐person (ICC = 0.89) samples. In the remote sample, greater acceleration was correlated with higher CDR®+NACC‐FTLD‐SB (r = 0.7,p = 0.003), and participants with motor features on the PSPRS had higher acceleration than those without (W = 11,p = 0.04).ConclusionThese findings provide preliminary support for the reliability and validity of the ALLFTD Mobile App tests of motor function. Replication in a larger sample is required.