Synucleinopathy-like Clinical Features and Biologically Defined Synucleinopathy in Psp-parkinsonism: An Imperfect Match

Synucleinopathy-like Clinical Features and Biologically Defined Synucleinopathy in Psp-parkinsonism: An Imperfect Match | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Synucleinopathy-like Clinical Features and Biologically Defined Synucleinopathy in Psp-parkinsonism: An Imperfect Match Celia*# Painous, Andrea* Martínez, Ana Camara, Manel Fernández, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8470662/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Whether synucleinopathy-like (syn-like) symptoms match biologically-defined synucleinopathy in PSP-parkinsonism (PSP-P) vs. Parkinson’s disease (PD) remains unexplored. We studied 80 subjects: 20 PSP-P, 20 PSP-Richardson-syndrome (PSP-RS), 20 PD, and 20 controls (CS). Procedures included specific smell-testing, structured interview by a sleep specialist, orthostatic-stress test, specific dysautonomia scale, CSF-α-synuclein seed-amplification-assay (asyn-SAA) and neurofilament-levels (NfL). Frequency of syn-like symptoms was low in CS+PSP-RS, intermediate in PSP-P, and high in PD. Premotor probable-RBD and orthostatic hypotension favoured PD, whereas probable-RBD after motor onset and higher pupillomotor dysautonomia scale scores predominated in PSP groups. NfL peaked in PSP-RS, not differing among PSP-P, PD and CS. asyn-SAA was 100% positive in PD, 100% negative in CS+PSP-RS, and positive in 24% PSP-P. Not all clinically-syn-like PSP-P cases were asyn-SAA positive, and vice versa. In summary, while partly overlapping with PD (including mild neurodegeneration as per NfL), syn-like symptoms do not always match biological synucleinopathy in PSP-P. Health sciences/Diseases Health sciences/Neurology Biological sciences/Neuroscience Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Neurodegenerative parkinsonisms are classified into synucleinopathies (Parkinson’s disease (PD) and multiple system atrophy), and 4-repeat tauopathies (4R-tau, progressive supranuclear palsy (PSP) and corticobasal degeneration). 1 PSP was first described as a single clinicopathological entity, 2 and this classical form later termed Richardson’s syndrome (PSP-RS) remained the only recognized phenotype for decades until other variants were formally incorporated into the revised diagnostic criteria. 3 Among these, PSP-parkinsonism (PSP-P) is of particular interest given its clinical overlap with PD, including, in part of the cases, asymmetric parkinsonism with rest tremor, levodopa responsiveness, and delayed ocular motor involvement, often leading to misdiagnosis. 4 As a suggested additional clue to differentiate PD from PSP, several non-motor symptoms have been reported as highly predictive of an underlying α-synucleinopathy, notably hyposmia, 5 rapid eye movement sleep behaviour disorder (RBD), 6,7 autonomic dysfunction 8,9 and visual hallucinations. 10 However, these non-motor clinical features suggestive of synucleinopathy (syn-like) have been mostly compared between PD and PSP-RS or healthy controls, leaving the differences between PD and PSP-P insufficiently characterized. 11 This gap is clinically relevant, as these features in PSP-P may hinder differentiation from PD and contribute to diagnostic uncertainty. Beyond clinical features, biomarker research has made substantial advances. Seed amplification assay for α-synuclein (asyn-SAA) demonstrates excellent sensitivity and specificity for PD, 12–16 but interpretation in PSP is complicated by frequent co-pathology. 17–20 Similarly, cerebrospinal fluid (CSF) and serum neurofilament light chain (NfL) levels are consistently elevated in PSP, but are nonspecific markers of disease severity and progression. In this vein, we have recently observed that PSP-P cases feature synuclein co-pathology as per SAA in around 20% of cases and that early, suggestive, and hence less aggressive PSP cases have significantly lower NfL levels than cases with more established and aggressive disease. 20 So far, the combined association of syn-like clinical features and biologically defined synucleinopathy (as per asyn-SAA) in PSP-P vs. PD remains largely unexplored. Addressing this knowledge gap is essential to interpret clinical and biomarker findings in clinical practice and, eventually, to improve the diagnostic accuracy between these entities. Accordingly, we aimed to thoroughly assess syn-like features (hyposmia, RBD, autonomic dysfunction and visual hallucinations) along with CSF asyn-SAA and NfL in PSP-P compared to PD, PSP-RS and control subjects. METHODOLOGY Study Design : this is a cross-sectional study conducted at the Parkinson's Disease and Movement Disorders Unit of Hospital Clinic in Barcelona between November 2023 and June 2025. Participants : we included a total of 80 participants: 20 subjects with a diagnosis of PSP-RS, 20 with PSP-P, 20 with PD and 20 subjects without known neurodegenerative disease or major psychiatric disorder (CS). Subjects with PSP and PD met the category of “probable” or “clinical definite” of their respective diagnostic criteria 3,5 and presented a disease duration of at least three years to reduce the likelihood of misdiagnosis in early stages. PSP (n=40) and PD (n=11) were consecutively recruited from a longitudinal, well-characterized cohort recently published the Barcelona PSP Registry. 20 The remaining PD participants were recruited consecutively from our outpatient clinic, and CS were relatives of parkinsonian patients if those were functionally independent (n=12), acquaintances of the investigator team (n=3), or participants in a previous biomarker study (n=5). 17 Individuals with dementia or a Montreal Cognitive assessment (MoCA) 21 <18, vascular parkinsonism, 22 or drug-induced parkinsonism were excluded. All patients provided written informed consent. Clinical assessments: We collected demographic and clinical variables such as sex, age at symptoms onset, age at baseline visit, disease duration at inclusion and both past and current medication. Motor function was evaluated in CS and PD with the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) 23 and in PSP with the PSP rating scale (PSPRS). 24 Hoehn and Yahr (HY) rating scale, 25 MoCA and Hospital Anxiety and Depression Scale (HADS) 26 were administered to all participants. Hyposmia was evaluated subjectively by asking the patient whether they experienced it or not, and with the University of Pennsylvania Smell Identification Test (UPSIT) 27 Spanish version. The UPSIT is a standardized multiple-choice scratch-and-sniff test consisting of four test booklets with 10 items each. Hyposmia, as assessed by the UPSIT, was defined as a score at or below the 15th percentile for age and sex. 28 Sleep evaluation: A structured interview by a neurologist with expertise in sleep disorders (JS) was carried out with the patient and bed-partner or family members assessing current sleep habits and complaints such as sleep-onset insomnia (difficulty falling asleep within 30 minutes); sleep fragmentation (more than two awakenings of >15 minutes); early awakening (waking up > 2 h earlier than desired); excessive daytime sleepiness (difficulty to stay awake during the day resulting in unintended episodes of sleep); and restless legs syndrome (RLS) (following the International Restless Legs Syndrome Study Group criteria). 29 The diagnosis of probable RBD was made clinically and only in the absence of symptoms suggestive of severe sleep apnea or restless legs syndrome. We distinguished two RBD patterns: Full RBD (fRBD)was defined as the presence of vivid dreams with dramatic or violent content, associated with vigorous and abrupt movements (appearing to mirror dream content) and shouting or vocalizations. Incomplete RBD (inRBD) was defined as the presence of vocalizations/shouting without prominent limb movements or with only subtle ones, in the absence of vivid dreams of violent or dramatic nature. We also collected the time interval (years) between the reported appearance of RBD in relation to motor symptoms onset. Sleep questionnaires. Sleep quality was also assessed with the Pittsburgh Sleep Quality Index (PSQI) 30 and daytime sleepiness with the Epworth Sleepiness Scale (ESS). 31 Autonomic symptoms evaluation: Orthostatic hypotension (OH) was evaluated with an orthostatic test and defined as a drop in systolic blood pressure of ≥20 mmHg or diastolic blood pressure of ≥10 mmHg within 3 minutes of standing up. 32 Nocturia was assessed by asking the patient for the number of nocturnal micturitions and was subsequently categorized as: absent (0 voids/night), mild (1–2 voids/night), or severe (≥3 voids/night). The Scales for Outcomes in Parkinson’s disease-Autonomic Dysfunction (SCOPA-AUT) 33 the total and individual domains scores were analysed. Finally, the Tottori University Hallucination Rating Scale (TUHARS) was used to evaluate the presence of hallucinations. 34 CSF biomarkers CSF-NfL and CSF asyn-SAA were previously performed as part of the Barcelona PSP Registry. 20 Briefly, CSF-NfL levels were measured with a commercial ELISA kit (Umandiagnostics, Sweden). The samples were run together with blank (sample diluent), the prepared calibrator solutions, and the appropriate control, always in duplicate (a single concentration value in pg/mL was calculated as the mean of the duplicates; all with a variation coefficient <20%). Regarding CSF asyn-SAA, positivity was defined as ≥2 of 3 replicates over 2SDs above the mean of relative fluorescence units (RFUs) in CS at 120h. 17 Postmortem neuropathological assessment See supplementary Methods. Statistics Qualitative variables are presented as frequencies and were compared by means of Fisher’s exact test. Quantitative data are presented as median/interquartile range (IQR) and were compared using Kruskal–Wallis test or Mann Whitney’s U-test, as appropriate. For statistical purposes, HY was converted to a binary variable as HYbin: I-II vs. III-V. Univariate logistic regression models were applied to explore variables discriminating between diagnostic groups, reporting odds ratios (OR), 95% confidence intervals (95% CI), and area under the receiver operating characteristic curve (AUC). Diagnostic performance of composite variables was evaluated through sensitivity, specificity, positive and negative predictive values. Agreement between subjective and objective hyposmia was analysed using Cohen’s κ. Statistical tests were two-tailed, with significance set at ≤ 0.05, corrected for multiple comparisons by false-discovery rate (p-FDR). 35 For exploratory subanalyses involving smaller sample sizes, results were reported without FDR correction (p-no FDR) due to the limited statistical power. Data analysis was carried out using Stata 16.0 (Stata Corp) for Windows and IBM SPSS statistics software version 24.0 (Armonk, NY:IBM Corp). Ethics Statement The study was approved by the Ethics Committee of Hospital Clínic de Barcelona (CEIm; approval number HCB/2020/0256). All participants provided written informed consent prior to inclusion. The study was conducted in accordance with the Declaration of Helsinki and its later amendments. RESULTS General demographic and clinical characteristics The median age of the population studied was 70 [66–75], and 43% were women, with no significant differences across groups. Median PSPRS scores were 26 [ 18 – 29 ] in PSP-P and 34 [ 24 – 41 ] in PSP-RS, while UPDRS-III scores in PD were 20 [ 14 – 24 ]. PSP-RS were more cognitively impaired and presented a higher HY than the rest. No significant differences were observed in anxiety scores (HADS-A) across groups, whereas patients with PD, PSP-P and PSP-RS scored higher on depression (HADS-D) compared to CS. In one patient with PSP-RS, the diagnosis was pathologically confirmed. See Table 1 . Table 1 Summary of assessments by diagnostic groups CS N = 20 PD N = 20 PSP-P N = 20 PSP-RS N = 20 Significant p-FDR values Age 69 [ 61 – 71 ] 71 [64–77] 69 [66–76] 71 [68–75] Sex (women %) 45% 40% 45% 40% Disease duration (years) NA 6 [ 3 – 9 ] 7 [ 3 – 10 ] 4 [ 3 – 5 ] MoCA 27 [ 26 – 28 ] 26 [ 24 – 28 ] 27 [ 24 – 28 ] 22 [ 21 – 26 ] All groups: 0.021; CS vs. PSP-RS: 0.007; PD vs. PSP-RS: 0.077; PSP-P vs. PSP-RS: 0.028 HY < 3 (%) NA 100% 75% 10% All groups: <0.001; PD vs. PSP-P: 0.047; PD vs. PSP-RS: <0.001; PSP-P vs. PSP-RS: <0.001 PSQI 3.5 [2.5–4.5] 6 [ 4 – 10 ] 9 [7–12.5] 9 [5.5–14] All groups: 0.0002; PD vs. CS p = 0.009; PSP-P vs. CS p = 0.0002; PSP-RS vs. CS p = 0.0002 HADS-A 5.5 [ 2 – 7 ] 6 [3.5–7] 4.5 [3–9.5] 5 [3.5–10] HADS-D 2 [0–4] 5 [2.5–7] 7 [3–9.5] 7 [5–11.5] All groups: 0.00035; PD vs. CS p = 0.0079; PSP-P vs. CS p = 0.0005; PSP-RS vs. CS p = 0.00035 UPSIT percentile 25 [ 16 – 40 ] 5 [ 3 – 9 ] 9 [ 4 – 17 ] 11 [ 8 – 18 ] All groups: <0.001; CS vs. PD: <0.001; CS vs. PSP-P: 0.001; CS vs. PSP-RS: 0.004; PD vs. PSP-RS: 0.006 UPSIT ≤ 15th percentile 15% 85% 75% 60% All groups: <0.001; CS vs. PD: <0.001; CS vs. PSP-P: <0.001; CS vs. PSP-RS: 0.014. fRBD + inRBD 0% 65% 45% 35% All groups: 0.004; CS vs. PD: <0.001; CS vs. PSP-P: 0.019; CS vs. PSP-RS: 0.077 Orthostatic hypotension 0% 40% 0% 10% All groups: 0.001; CS vs PD: 0.006; PD vs PSP-P: 0.006; PD vs PSP-RS: 0.098 SCOPA-AUT 8 [ 5 – 11 ] 15 [ 9 – 21 ] 23 [ 14 – 27 ] 23 [ 17 – 29 ] All groups: <0.001; CS vs. PD: 0.004; CS vs. PSP-P: <0.001; CS vs. PSP-RS: 0.002; PD vs. PSP-P: 0.028; PD vs. PSP-RS: 0.021 Nicturia severe 5% 35% 35% 42% All groups: 0.019; CS vs. PD: p 0.053; CS vs. PSP-P: p = 0.019; CS vs. PSP-RS: p = 0.019 TUHARS 0 [0–0] 0.5 [0–1] 0 [0–1] 0 [0–0.5] CS: control subjects; fRBD: full REM sleep behaviour disorder; HADS: Hospital Anxiety and Depression Scale, -A: anxiety, -D: depression; HY: Hoehn and Yahr rating scale; inRBD: incomplete REM sleep behaviour disorder; MoCA: Montreal Cognitive assessment; NA: Not Applicable; p-FDR: p-values corrected by false discovery rate; PD: Parkinson disease; PSQI: Pittsburgh Sleep Quality Index; PSP-P: progressive supranuclear palsy, parkinsonian variant; PSP-RS: progressive supranuclear palsy, Richardson syndrome variant; SCOPA-AUT: Scales for Outcomes in Parkinson Disease–Autonomic; TUHARS: Tottori University Hallucination Rating Scale; UPSIT: University of Pennsylvania Smell Identification Test. Hyposmia UPSIT percentiles were lower in PD: 5 [ 3 – 9 ], PSP-P: 9 [ 4 – 17 ], PSP-RS: 11 [8–18, compared with CS 25: [ 16 – 40 ]; overall p-FDR < 0.001) (Fig. 1 ; Table 1 ). PSP-RS performed better than PD (p-FDR = 0.006), whereas PSP-P did not differ significantly from either PD or PSP-RS. The proportion of individuals equal or below the 15th percentile was 85% in PD, 75% in PSP-P, 60% in PSP-RS, and 15% in CS ( Suppl. Table 1 ). The agreement between subjective and UPSIT-defined hyposmia varied across groups ( Suppl. Table 1 ). CS showed the highest concordance (κ = 0.46, p = 0.007), followed by PSP-P (κ = 0.37, p = 0.035), whereas concordance was low and non-significant in PD (κ = 0.08) and PSP-RS (κ = 0.15). If subjective hyposmia alone had been considered, misclassification would have occurred in 10% of CS, 30% of PD and PSP-P, and 45% of PSP-RS cases. Sleep disturbances There were no significant differences in the use of sleep-related medications among PD, PSP-P and PSP-RS, including benzodiazepines or antipsychotics (Table 2 ). Table 2 Medication profile across diagnostic groups Use of antiparkinsonian and neuropsychiatric medications in each study group. Data are expressed as the number and percentage of patients receiving each drug class. Levodopa equivalent daily dose (LEDD) is presented as median [IQR]. Neuropsychiatric medications include benzodiazepines, antidepressants (not limited to those with sedative effects), and antipsychotics. CS PD PSP-P PSP-RS CS vs PD p-FDR CS vs PSP-P p-FDR CS vs PSP-RS p-FDR PD vs PSP-P p-FDR PD vs PSP-RS p-FDR PSP-P vs PSP-RS p-FDR All groups p-FDR LEDD (mg/d) 0 800 [700–940] 775 [600–1100] 850 [575–1050] < 0.001 < 0.001 < 0.001 0.912 0.912 0.912 < 0.001 Benzodiazepines n (%) 3 (15%) 8 (40%) 8 (40%) 4 (20%) 0.247 0.247 0.873 0.2475 1.000 0.2475 0.215 Antidepressants n (%) 4 (20%) 6 (30%) 12 (60%) 13 (65%) 0.6312 0.033 0.024 0.0855 0.054 0.751 0.020 Antipsychotics n (%) 0 (0%) 1 (5%) 1 (5%) 5 (25%) 0.6936 0.6936 0.03 1.000 0.052 0.052 0.046 CS: control subjects; p-FDR: p-values adjusted for False Discovery Rate; PD: Parkinson’s disease; PSP: progressive supranuclear palsy; PSP-P: PSP-parkinsonism; PSP-RS: PSP-Richardson’s syndrome. Symptoms compatible with fRBD were present in 50% of PD, but only in 20% of each group of PSP. In contrast, inRBD was present similarly in all patient groups (25% of PSP-P and 15% of PD and PSP-RS; Fig. 2 ). When full and incomplete RBD were pooled, the prevalence differed significantly across groups (p-FDR = 0.004), with higher frequencies in PD and PSP-P compared to CS (p-FDR < 0.001 and 0.019, respectively). No significant differences were observed between PD, PSP-P and PSP-RS (Table 1 ). Among participants with probable RBD, the parasomnia appeared after the motor symptoms of the disease more frequently in PSP than in PD (89% of PSP-P, 86% of PSP-RS, and 38% of PD), with a significant overall difference (p-no FDR = 0.030) and pairwise comparisons showing significance for PSP-P vs. PD (p-no FDR = 0.031) and a trend for PSP-RS vs. PD (p-no FDR = 0.070), but no difference between PSP-P and PSP-RS (p-no FDR = 1.000) (Fig. 2 ). Excessive daytime sleepiness was more frequent in PD, followed by PSP-P and PSP-RS, and was less common in CS, while RLS occurred in 35% of PD, 26% of PSP-RS, 5% of PSP-P, and 16% of CS, with no difference between groups. Further details are available in the Supplementary Results & Suppl. Figure 1–2 . Autonomic symptoms An abnormal orthostatic test was observed more frequently in PD (40%) than in CS (0%, p-FDR = 0.006) and PSP-P (0%, p-FDR = 0.006). Two PSP-RS, one was the neuropathologically confirmed, also showed abnormal results, both receiving high doses of dopaminergic agents (> 2g per day). Nocturia was commonly reported in PD, PSP-P and PSP-RS, being severe (≥ 3 voids/night) in 42% of PSP-RS and 35% in PSP-P and PD, compared to only 5% in CS. SCOPA-AUT scores were highest in PSP-P (23 [ 14 – 27 ]) and PSP-RS (23 [ 17 – 29 ]), followed by PD (15 [ 9 – 21 ]) and CS (8 [ 5 – 11 ]; overall p-FDR < 0.001). PD, PSP-P and PSP-RS scored higher than CS (all p-FDR ≤ 0.002), and both PSP groups scored higher than PD (p-FDR = 0.024 and p-FDR = 0.015), with no significant difference between them (p-FDR = 0.808). Analysis of the individual domains showed that gastrointestinal, urinary and cardiovascular functions were significantly more impaired in PD, PSP-P and PSP-RS compared to CS. In the gastrointestinal domain, PSP-RS scored worse than PD, but this trend turned borderline significant after FDR correction (p-FDR = 0.072). Pupillomotor dysfunction was significantly higher in PSP-P and PSP-RS compared with PD (p-FDR = 0.034 & p-FDR = 0.002, respectively) and to CS (p-FDR < 0.001). No significant differences were observed in either the sexual or termoregulatory domains ( Suppl. Figure 3 ). Hallucinations Hallucinations (TUHARS) were infrequent across all diagnostic groups (Table 1 ). Discriminative clinical features Univariate logistic regression analyses are summarized in Suppl. Tables 2–4 and visually represented in the forest plot (Fig. 3 ). Lower UPSIT scores (OR = 0.91, p-no FDR = 0.032), orthostatic hypotension (OR = 12.7, p-no FDR = 0.003), fRBD (OR = 4.0, p-no FDR = 0.020) and premotor probable RBD (OR = 11.2, p-no FDR = 0.011) significantly discriminated PD from PSP. Specifically in the comparison between PD and PSP-P, fRBD (OR = 4.0, p-no FDR = 0.053) and premotor probable RBD (OR = 12.8, p-no FDR = 0.034) showed the strongest discriminative capacity, with AUC values of 0.65 and 0.75, respectively. In the comparison between PSP-P and PSP-RS, none of the syn-like features significantly discriminated between the two phenotypes. A simple 3-item mini-score ( fRBD , premotor probable RBD, UPSIT ≤ 15th percentile; 0–3 points) showed fair discrimination between PD and PSP-P (AUC = 0.71, 95% CI 0.57–0.86). Using a prespecified cut-off ≥ 2 points yielded 50% sensitivity, 85% specificity, PPV 0.77 and NPV 0.63 (AUC = 0.68, 95% CI 0.54–0.81). CSF biomarkers We obtained CSF from 5 controls, 11 PD, 17 PSP-P, and 17 PSP-RS participants. All PD were positive results for asyn-SAA, followed by 24% of PSP-P and none of both PSP-RS and controls (PSP-P vs PD p < 0.001; PSP-P vs PSP-RS p = 0.103). Among PSP-P, asyn-SAA positivity (4/17, 24%) was not associated with greater motor (PSPRS: 28 [ 22 – 33 ] vs. 27 [ 22 – 29 ]; p-FDR = 0.69) or cognitive impairment (MoCA: 28 [ 23 – 29 ] vs. 24 [ 22 – 28 ]; p-FDR = 0.61), nor with significantly higher frequencies of hyposmia (100% vs. 62%; p-FDR = 0.26), pooled probable RBD (75% vs. 31%; p-FDR = 0.25), or orthostatic hypotension (0% in both groups), although subgroup sample sizes were small. CSF-NfL levels differed significantly across groups (p-FDR < 0.001). Median values were 832 [497–870] pg/mL in CS, 880 [509–1285] pg/mL in PD, 1046 [604–1193] pg/mL in PSP-P, and 2269 [1699–3479] pg/mL in PSP-RS. Pairwise comparisons showed higher NfL in PSP-RS compared with CS (p-FDR = 0.039), PD (p-FDR < 0.001), and PSP-P (p-FDR < 0.001), whereas no significant differences were found between PD or PSP-P with CS. Within the PSP-P group, CSF NfL levels did not differ significantly between asyn-SAA–negative (n = 13; median 775 [599–1193] pg/mL) and asyn-SAA–positive cases (n = 4; median 1088 [893–1230] pg/mL; p-FDR = 0.57), although the number of patients was small. Pathological case One of the participants died and was a brain donor. The disease began at age 63 with early falls, difficulty looking downward, and reduced facial expressiveness. At the time of evaluation, the patient exhibited supranuclear vertical gaze palsy (both upward and downward), moderate bradykinesia, resting tremor of the left arm, unsteady gait, and impaired postural reflexes, fulfilling clinical criteria for probable PSP-Richardson’s syndrome. The UPSIT score corresponded to the 16th percentile, the orthostatic blood pressure test was abnormal, and a probable inRBD pattern was identified. Altogether, this profile was consistent with syn-like clinical features, with olfactory performance lying close to the predefined hyposmia cut-off (see Methods). However, CSF asyn-SAA was negative, as were Alzheimer’s biomarkers (beta amyloid 890 pg/ml, tau 256 pg/ml, pTau 30 pg/ml). CSF-NfL were increased (3479 pg/ml). Neuropathological examination revealed a predominant 4-repeat tauopathy consistent with PSP (Kovacs stage 5/6 and Williams stage 10/12). Tau pathology was abundant in the ventral medullary tegmentum, including the gigantocellular nucleus, and in the pontine tegmentum, involving the locus coeruleus and the subcoeruleus nucleus. These regions, relevant for syn-like features afforded by this patient, also showed globose neurofibrillary tangles, neurites, and pretangles. These neuropathological features exceeded those from two other PSP cases from the Neurological Tissue Bank used for comparison purposes. In keeping with negative asyn-SAA, no α-synuclein was identified in general, including specific assessment of the medulla and the pons. TDP-43 pathology was absent too. Alzheimer’s disease–related changes (A1B1C0) and cerebrovascular pathology were low-grade and mild, and thus deemed unlikely to account for clinical features. DISCUSSION In this study, non-motor features classically linked to α-synucleinopathies followed a gradient across PD > PSP-P > PSP-RS, with a higher-than-expected frequency in PSP, particularly in PSP-P. While hyposmia, probable RBD, and autonomic symptoms were common in PD, PSP-P and PSP-RS, the timing and pattern of these manifestations retained diagnostic value: premotor RBD and orthostatic hypotension were mainly associated with PD, whereas in patients with PSP (both, PSP-P and PSP-RS), probable RBD typically appeared after motor onset and SCOPA-AUT scores were higher, mainly due to greater impairment in pupillomotor domain. At the biomarker level, despite a proportion of asyn-SAA positive PSP-P cases, the results still clearly distinguished PSP-P from PD, whereas CSF-NfL did not differentiate between these two groups. Finally, while PSP-P group featured a proportion of patients with syn-like clinical features and part of cases with positive asyn-SAA, clinical and biological synucleinopathy did not match, suggesting that underlying asyn co-pathology may not account (at least not in all instances) for syn-like symptoms in PSP-P. Regarding hyposmia, early clinical series suggested it was absent or rare in PSP, 4,36–39 reinforcing its use as a marker of synucleinopathies. However, we have encountered hyposmia in 67.5% of our PSP patients, consistent with recent reports showing a higher-than-expected frequency, sometimes approaching that of PD, 40,41 although none specifically addressed PSP-P. Neuropathological data provide plausible explanations for the occurrence of hyposmia in PSP. Tau pathology has been described in the rhinencephalon of PSP patients, 39,42 suggesting a direct contribution to olfactory impairment, yet hyposmia was not observed in all patients with involvement of these regions. 39 Alternatively, olfactory loss in PSP may reflect concomitant Lewy body copathology, as higher α-synuclein burden has been correlated with lower UPSIT scores. 42 In contrast to PD, where early α-synuclein involvement of the olfactory bulb is well established, 43 PSP does not typically show this pattern, supporting a more central mechanism possibly related to brainstem or rhinencephalic integrative structures. 39,42,44 Importantly, in our cohort, subjective hyposmia and UPSIT-defined hyposmia correlated only moderately in PSP-P and controls, but not in PSP-RS or PD. This discordance suggests that relying solely on subjective complaints risks underestimating the true prevalence of olfactory loss. As for RBD, in PSP polysomnographic studies have reported variable prevalence (8% to 35%). 45–48 Converging evidence indicates that RBD emerges when key regions such as the locus coeruleus/subcoeruleus complex, the ventromedial medulla or the pedunculopontine area are affected. 49–52 Supporting this, our group described a pathologically confirmed PSP case with RBD, showing tau pathology in these regions. 53 Altogether, these observations suggest that dysfunction of specific brainstem nuclei, rather than the protein aggregate type, underlies the pathophysiology of RBD. A novel aspect of our study is that, beyond assessing probable RBD across PSP phenotypes, we found that it tended to precede motor onset in PD, whereas it appeared after motor onset in PSP. Logistic univariate regression models confirmed this pattern, showing that premotor RBD strongly discriminated PD from PSP and specifically PD from PSP-P. This temporal relationship with the motor symptoms likely reflects the distinct neuroanatomical progression of pathology in both diseases: whereas α-synuclein pathology in PD seems to follow a caudal-to-rostral trajectory involving early degeneration of the pontomedullary REM-atonia network, 43 tau pathology in PSP originates in the basal ganglia and midbrain, affecting these lower brainstem structures in later stages. 54 Moreover, RBD manifestations in PSP were often subtler in our study, a finding in agreement with a previous work, 45 that reported that none of their PSP patients exhibited overt dream-enactment behaviors despite the presence of REM sleep without atonia in video-PSG. They speculated that more severe motor and cognitive impairment in PSP might mask RBD manifestations, and that PSP patients may experience less vivid or violent dream content compared to PD. Regarding dysautonomic function, both PSP variants showed significantly higher SCOPA-AUT scores than PD, in line with recent studies. 55,56 Pupilomotor impairment, which may manifest with photophobia or blurred vision, is consistently more pronounced in PSP than in PD, and these visual complaints can emerge several years before the clinical diagnosis of parkinsonism. 57 Studies using pupillography and chromatic pupillometry show smaller dark-adapted pupils and slower light-reflex responses in PSP. 58,59 This has been attributed to the more extensive tau-mediated degeneration of midbrain pupillary control centres, especially the pretectal Edinger-Westphal complex and adjacent autonomic pathways. 60 Reports on orthostatic hypotension in PSP have been inconsistent. In our cohort, OH was absent in PSP-P and rare in PSP-RS, in contrast with 40% prevalence in PD. These findings are aligned with previous studies showing low prevalence of neurogenic OH in PSP, 55,56,61,62 although higher frequencies have been reported by other authors. 63,64 These discrepancies likely reflect methodological differences such as diagnostic criteria, exclusion of comorbidities, and dopaminergic medication use. 65 The prevalence of hallucinations was low across all groups. In PSP, hallucinations are generally uncommon but not exceptional as have been shown in autopsy-based data 10,66 and in clinical studies too. 67 In PD, a higher frequency would usually be expected; in our cohort, however, the low rate is plausibly explained by the exclusion of individuals with significant cognitive impairment, given the well-described association between cognitive decline and hallucinations in synucleinopathies. 68,69 In our cohort, CSF-NfL was higher in PSP-RS than in PSP-P and PD, which showed overlapping values. This is consistent with extensive literature demonstratig that PSP-P constitutes a lesser aggressive phenotype with slower progression and longer survival. 70,71 Regarding asyn-SAA, both PSP-RS and PSP-P showed significantly lower positivity than PD, although occasional positivity in PSP-P underscores that this assay cannot be used in isolation to distinguish both entities. In this setting, 4R-tau biomarkers, like tau-PET or tau-SAA would be of valuable interest. This study is not without limitations. First, the sample size was modest, specifically regarding CSF, not available for all cases, and when stratifying by phenotype, limiting statistical power for subgroup analyses. Furthermore, we only have neuropathological confirmation of one case and specific 4R-tau biomarkers were not available. Hence, caution is required when interpretating our results overall, and the non-significant trends, in particular. Second, RBD was diagnosed clinically rather than by video-PSG, which remains the gold standard. However, structured interviews by an experienced sleep neurologist incorporating information from both the patient and the bed partner and clinically excluding confounding disorders (e.g., severe sleep apnea or restless legs syndrome) has been proven to be specific. 72 Third, autonomic dysfunction was assessed by questionnaire and orthostatic testing, but no additional evaluations were performed. Fourth, olfactory assessment was limited to the UPSIT, which, while standardized, can be influenced by cultural and cognitive status. Despite these limitations, this study has several notable strengths. The inclusion of 20 patients per PSP phenotype represents a relatively large and well-balanced cohort for a rare disorder. All participants underwent detailed and harmonized clinical characterization, with minimal missing data. Furthermore, the parallel assessment of sleep, olfactory, and autonomic domains, together with CSF biomarker in a subset of the cohort, provides a comprehensive multidimensional view of PSP-P and PSP-RS that is rarely achieved in single-center studies. In conclusion, our findings reveal that non-motor features traditionally linked to α-synucleinopathies are also common in PSP, particularly in the PSP-P variant, which also has greater proportion of biologically defined synucleinopathy. However, syn-like clinical features did not completely match with biologically defined synucleinopathy, suggesting overlapping yet distinct pathogenic mechanisms. Hence, syn-like clinical features might be determined by synuclein co-pathology in some cases, whereas in some others it could be the topographical involvement of specific brain regions by primary tauopathy what might account for these symptoms. Further longitudinal studies including 4R-tau wet or imaging markers, objective dysautonomia and sleep assessments, and more pathologically confirmed cases, are warranted to confirm or not our observations suggesting that not only concomitant synucleinopathy, but also strategic regional tau deposition, underlie the phenotypic overlap between PD and PSP-P. Declarations Data Availability: The datasets generated and/or analyzed during the current study are not publicly available due to the inclusion of confidential and sensitive patient information, but they are available from the corresponding author on reasonable request. ACKNOWLEDGEMENTS: We thank all patients that willfully participated in the Barcelona PSP Registry. This study was funded by “La Marató de TV3” Foundation. The funder played no role in the study design, data collection, analysis, interpretation of data, or writing of the manuscript. We are indebted to the Biobanc-Hospital Clinic-FRCB-IDIBAPS for samples and data procurement. MF is funded by Institut de neurociències de la Universitat de Barcelona, Maria de Maeztu CEX2021-001159-M / financiada por MICIU/AEI / 10.13039/501100011033. Authors' Roles: List all authors along with a clarification of role(s): e.g. design (D), execution (E), analysis (A), writing (W), editing of final version of the manuscript (R). CP: D, E, A, W, R AM: E, A, W, R AC: E (research nurse coordinator), R MF, LdM, JPM: E, A (NfL analysis), R RRG, LN: E, A (asyn-SAA analysis), R MJM, EM, ASG, APS, AG, FV, ET, NC, SJ, CPS, TD, AL, CB: E, R (Expert opinion, patient recruitment) IA, LMP: A (Postmortem analysis), R JS: D, A, R (principal investigator) YC: D, A, R (principal investigator) Barcelona PSP-Registry CONSORTIUM: patient Recruitment Financial Disclosures of all authors (for the preceding 12 months) All authors declare no financial or non-financial competing interests. 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UBNeuro.","correspondingAuthor":true,"prefix":"","firstName":"Compta#","middleName":"","lastName":"Yaroslau","suffix":""}],"badges":[],"createdAt":"2025-12-29 08:08:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8470662/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8470662/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100401258,"identity":"34f25e2b-5cfd-4b92-83db-f08a19c87119","added_by":"auto","created_at":"2026-01-16 11:58:49","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":565549,"visible":true,"origin":"","legend":"","description":"","filename":"synlikefeaturesbiologicalsynucleiniopathyinPSPP.docx","url":"https://assets-eu.researchsquare.com/files/rs-8470662/v1/af2d930c451d469bbc2c22c4.docx"},{"id":100401102,"identity":"e2ef5934-9c85-4a24-9515-cabef8ba4439","added_by":"auto","created_at":"2026-01-16 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11:58:42","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":211217,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8470662/v1/3ef6c8abea4fcc3b19d9386f.html"},{"id":100400788,"identity":"6b469592-ee20-415c-bc4f-8f7afd031930","added_by":"auto","created_at":"2026-01-16 11:58:26","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":127651,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eUPSIT percentiles, RBD and CSF asyn-SAA across diagnostic groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUPSIT performance (percentile) \u003cstrong\u003e(A)\u003c/strong\u003e and prevalence of RBD (full + incomplete) \u003cstrong\u003e(B)\u003c/strong\u003eshow a gradient of impairment across groups, with the lowest scores in PD, followed by PSP-P, PSP-RS, and CS. Panel \u003cstrong\u003e(C)\u003c/strong\u003e shows CSF asyn-SAA positivity across groups.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003easyn-SAA = α-synuclein seed-amplification assay; CS = control subjects; CSF = cerebrospinal fluid; PD = Parkinson’s disease; p-FDR = false-discovery-rate–corrected p-value; PSP-P = PSP-parkinsonism; PSP-RS = PSP-Richardson’s syndrome; RBD = REM sleep behaviour disorder; UPSIT = University of Pennsylvania Smell Identification Test.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470662/v1/179ddd6d6502e0b00d935b7b.jpeg"},{"id":100401094,"identity":"a5080f82-84f1-4b7e-b3d9-46c4117e72b4","added_by":"auto","created_at":"2026-01-16 11:58:41","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":68845,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTiming of RBD onset across PD, PSP-P and PSP-RS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTime of appearance (in years) of probable RBD relative to motor symptom onset in PD, PSP-P, and PSP-RS. Blue circles represent \u003cem\u003einRBD\u003c/em\u003e and red triangles \u003cem\u003efRBD\u003c/em\u003e. The horizontal black line marks the onset of motor symptoms (time = 0). Positive values on the y-axis indicate probable RBD onset after motor onset (postmotor), whereas negative values indicate probable RBD preceding motor onset (premotor). Premotor RBD predominated in PD, while in PSP-P and PSP-RS, probable RBD appeared after motor onset in all but two cases. Severity of probable RBD was worse in PD than in PSP.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003efRBD: full RBD; inRBD: incomplete RBD; PD: Parkinson’s disease; PSP: progressive supranuclear palsy; PSP-P: PSP-parkinsonism; PSP-RS: PSP-Richardson’s syndrome; RBD: rapid eye movement sleep behavior disorder.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470662/v1/06d717bd04a686e6c7cd8c77.jpeg"},{"id":100400422,"identity":"89bc4c07-57a0-4ee3-81e5-403baf5d7a92","added_by":"auto","created_at":"2026-01-16 11:58:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":79236,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot of significant univariate logistic regressions.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForest plot showing the significant univariate logistic regression models differentiating diagnostic groups. Odds ratios (log scale) with 95% confidence intervals are displayed for variables that reached statistical significance. The vertical dashed red line indicates the null value (OR = 1).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMoCA: Montreal Cognitive Assessment; OR: odds ratio; PD: Parkinson’s disease; PSP: progressive supranuclear palsy; PSP-P: PSP-parkinsonism; PSP-RS: PSP-Richardson’s syndrome; RBD: REM sleep behaviour disorder; fRBD: full RBD; UPSIT: University of Pennsylvania Smell Identification Test.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8470662/v1/c8e5fd6ffb95825598b43a80.png"},{"id":100594322,"identity":"8bde9c20-b776-4b40-84fa-372daae513a4","added_by":"auto","created_at":"2026-01-19 13:38:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1531891,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8470662/v1/805715b8-effa-419d-8a7d-87e1f6bbce2b.pdf"},{"id":100401215,"identity":"4b9de831-9ba8-4c96-9b31-83f0c4687db4","added_by":"auto","created_at":"2026-01-16 11:58:46","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":16486,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMethods.docx","url":"https://assets-eu.researchsquare.com/files/rs-8470662/v1/2f3b44c2b4b833105f5e5abc.docx"},{"id":100399566,"identity":"ca00a095-056b-4e64-b229-0e4d0038607e","added_by":"auto","created_at":"2026-01-16 11:57:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":355569,"visible":true,"origin":"","legend":"","description":"","filename":"SupplTablesFigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-8470662/v1/df4ee3899d04b5cb307383e4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSynucleinopathy-like Clinical Features and Biologically Defined Synucleinopathy in Psp-parkinsonism: An Imperfect Match\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eNeurodegenerative parkinsonisms are classified into synucleinopathies (Parkinson\u0026rsquo;s disease (PD) and multiple system atrophy), and 4-repeat tauopathies (4R-tau, progressive supranuclear palsy (PSP) and corticobasal degeneration).\u003csup\u003e1\u003c/sup\u003e PSP was first described as a single clinicopathological entity,\u003csup\u003e2\u003c/sup\u003e and this classical form later termed Richardson\u0026rsquo;s syndrome (PSP-RS) remained the only recognized phenotype for decades until other variants were formally incorporated into the revised diagnostic criteria.\u003csup\u003e3\u003c/sup\u003e Among these, PSP-parkinsonism (PSP-P) is of particular interest given its clinical overlap with PD, including, in part of the cases, asymmetric parkinsonism with rest tremor, levodopa responsiveness, and delayed ocular motor involvement, often leading to misdiagnosis.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAs a suggested additional clue to differentiate PD from PSP, several non-motor symptoms have been reported as highly predictive of an underlying α-synucleinopathy, notably hyposmia,\u003csup\u003e5\u003c/sup\u003e rapid eye movement sleep behaviour disorder (RBD),\u003csup\u003e6,7\u003c/sup\u003e autonomic dysfunction\u003csup\u003e8,9\u003c/sup\u003e and visual hallucinations.\u003csup\u003e10\u003c/sup\u003e However, these non-motor clinical features suggestive of synucleinopathy (syn-like) have been mostly compared between PD and PSP-RS or healthy controls, leaving the differences between PD and PSP-P insufficiently characterized.\u003csup\u003e11\u003c/sup\u003e This gap is clinically relevant, as these features in PSP-P may hinder differentiation from PD and contribute to diagnostic uncertainty.\u003c/p\u003e \u003cp\u003eBeyond clinical features, biomarker research has made substantial advances. Seed amplification assay for α-synuclein (asyn-SAA) demonstrates excellent sensitivity and specificity for PD,\u003csup\u003e12\u0026ndash;16\u003c/sup\u003e but interpretation in PSP is complicated by frequent co-pathology.\u003csup\u003e17\u0026ndash;20\u003c/sup\u003e Similarly, cerebrospinal fluid (CSF) and serum neurofilament light chain (NfL) levels are consistently elevated in PSP, but are nonspecific markers of disease severity and progression. In this vein, we have recently observed that PSP-P cases feature synuclein co-pathology as per SAA in around 20% of cases and that early, suggestive, and hence less aggressive PSP cases have significantly lower NfL levels than cases with more established and aggressive disease.\u003csup\u003e20\u003c/sup\u003e So far, the combined association of syn-like clinical features and biologically defined synucleinopathy (as per asyn-SAA) in PSP-P vs. PD remains largely unexplored.\u003c/p\u003e \u003cp\u003eAddressing this knowledge gap is essential to interpret clinical and biomarker findings in clinical practice and, eventually, to improve the diagnostic accuracy between these entities. Accordingly, we aimed to thoroughly assess syn-like features (hyposmia, RBD, autonomic dysfunction and visual hallucinations) along with CSF asyn-SAA and NfL in PSP-P compared to PD, PSP-RS and control subjects.\u003c/p\u003e"},{"header":"METHODOLOGY","content":"\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e: this is a cross-sectional study conducted at the Parkinson's Disease and Movement Disorders Unit of Hospital Clinic in Barcelona between November 2023 and June 2025.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e: we included a total of 80 participants: 20 subjects with a diagnosis of PSP-RS, 20 with PSP-P, 20 with PD and 20 subjects without\u0026nbsp;known neurodegenerative disease or major psychiatric disorder (CS). Subjects with PSP and PD met the category\u0026nbsp;of “probable” or “clinical definite” of their respective diagnostic criteria\u003csup\u003e3,5\u003c/sup\u003e and presented a disease duration of at least three years to reduce the likelihood of misdiagnosis in early stages. PSP (n=40) and PD (n=11) were consecutively recruited from a longitudinal, well-characterized cohort recently published the Barcelona PSP Registry.\u003csup\u003e20\u003c/sup\u003e The remaining PD participants were recruited consecutively from our outpatient clinic, and CS were relatives of parkinsonian patients if those were functionally independent (n=12), acquaintances of the investigator team (n=3), or participants in a previous biomarker study (n=5).\u003csup\u003e17\u003c/sup\u003e Individuals with dementia or a Montreal Cognitive assessment (MoCA)\u003csup\u003e21\u003c/sup\u003e \u0026lt;18, vascular parkinsonism,\u003csup\u003e22\u003c/sup\u003e or drug-induced parkinsonism were excluded. All patients provided written informed consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical assessments:\u0026nbsp;\u003c/strong\u003eWe collected demographic and clinical variables such as sex, age at symptoms onset, age at baseline visit, disease duration at inclusion and both past and current medication. Motor function was evaluated in CS and PD with the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III)\u003csup\u003e23\u0026nbsp;\u003c/sup\u003eand in PSP with the PSP rating scale (PSPRS).\u003csup\u003e24\u003c/sup\u003e Hoehn and Yahr (HY) rating scale,\u003csup\u003e25\u003c/sup\u003e MoCA and Hospital Anxiety and Depression Scale (HADS)\u003csup\u003e26\u003c/sup\u003e were administered to all participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHyposmia was evaluated subjectively by asking the patient whether they experienced it or not, and with the University of Pennsylvania Smell Identification Test (UPSIT)\u003csup\u003e27\u0026nbsp;\u003c/sup\u003eSpanish version. The UPSIT is a standardized multiple-choice scratch-and-sniff test consisting of four test booklets with 10 items each. Hyposmia, as assessed by the UPSIT, was defined as a score at or below the 15th percentile for age and sex.\u003csup\u003e28\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eSleep evaluation:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eA structured interview by a neurologist with expertise in sleep disorders (JS) was carried out with the patient and bed-partner or family members assessing current sleep habits and complaints such as sleep-onset insomnia (difficulty falling asleep within 30 minutes); sleep fragmentation (more than two awakenings of \u0026nbsp;\u0026gt;15 minutes); early awakening (waking up \u0026gt; 2 h earlier than desired); \u0026nbsp;excessive daytime sleepiness (difficulty to stay awake during the day resulting in unintended episodes of sleep); and restless legs syndrome (RLS) (following the International Restless Legs Syndrome Study Group criteria).\u003csup\u003e29\u003c/sup\u003e The diagnosis of probable RBD was made clinically and only in the absence of symptoms suggestive of severe sleep apnea or restless legs syndrome. We distinguished two RBD patterns: Full RBD (fRBD)was defined as the presence of vivid dreams with dramatic or violent content, associated with vigorous and abrupt movements (appearing to mirror dream content) and shouting or vocalizations. Incomplete RBD (inRBD) was defined as the presence of vocalizations/shouting without prominent limb movements or with only subtle ones, in the absence of vivid dreams of violent or dramatic nature. We also collected the time interval (years) between the reported appearance of RBD in relation to motor symptoms onset.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSleep questionnaires. Sleep quality was also assessed with the\u0026nbsp;Pittsburgh Sleep Quality Index (PSQI)\u003csup\u003e30\u003c/sup\u003e and daytime sleepiness with the Epworth Sleepiness Scale (ESS).\u003csup\u003e31\u003c/sup\u003e\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eAutonomic symptoms evaluation:\u0026nbsp;\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eOrthostatic hypotension (OH) was evaluated with an orthostatic test and defined as a drop in systolic blood pressure of ≥20 mmHg or diastolic blood pressure of ≥10 mmHg within 3 minutes of standing up.\u003csup\u003e32\u003c/sup\u003e\u003c/li\u003e\n \u003cli\u003eNocturia was assessed by asking the patient for the number of nocturnal micturitions and was subsequently categorized as: absent (0 voids/night), mild (1–2 voids/night), or severe (≥3 voids/night).\u003c/li\u003e\n \u003cli\u003eThe Scales for Outcomes in Parkinson’s disease-Autonomic Dysfunction (SCOPA-AUT)\u003csup\u003e33\u003c/sup\u003e the total and individual domains scores were analysed.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eFinally, the Tottori University Hallucination Rating Scale (TUHARS) was used to evaluate the presence of hallucinations.\u003csup\u003e34\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCSF biomarkers\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCSF-NfL and CSF asyn-SAA were previously performed as part of the Barcelona PSP Registry.\u003csup\u003e20\u003c/sup\u003e Briefly, CSF-NfL levels were measured with a commercial ELISA kit (Umandiagnostics, Sweden). The samples were run together with blank (sample diluent), the prepared calibrator solutions, and the appropriate control, always in duplicate (a single concentration value in pg/mL was calculated as the mean of the duplicates; all with a variation coefficient \u0026lt;20%). Regarding CSF asyn-SAA, positivity was defined as ≥2 of 3 replicates over 2SDs above the mean of relative fluorescence units (RFUs) in CS at 120h.\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePostmortem neuropathological assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSee supplementary Methods.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQualitative variables are presented as frequencies and were compared by means of Fisher’s exact test. Quantitative data are presented as median/interquartile range (IQR) and were compared using Kruskal–Wallis test or Mann Whitney’s U-test, as appropriate. For statistical purposes, HY was converted to a binary variable as HYbin: I-II vs. III-V. Univariate logistic regression models were applied to explore variables discriminating between diagnostic groups, reporting odds ratios (OR), 95% confidence intervals (95% CI), and area under the receiver operating characteristic curve (AUC). Diagnostic performance of composite variables was evaluated through sensitivity, specificity, positive and negative predictive values. Agreement between subjective and objective hyposmia was analysed using Cohen’s κ. Statistical tests were two-tailed, with significance set at ≤ 0.05,\u0026nbsp;corrected for multiple comparisons by false-discovery rate (p-FDR).\u003csup\u003e35\u003c/sup\u003e For exploratory subanalyses involving smaller sample sizes, results were reported without FDR correction (p-no FDR) due to the limited statistical power. Data analysis was carried out using Stata 16.0 (Stata Corp) for Windows and IBM SPSS statistics software version 24.0 (Armonk, NY:IBM Corp).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of Hospital Clínic de Barcelona (CEIm; approval number HCB/2020/0256). All participants provided written informed consent prior to inclusion. The study was conducted in accordance with the Declaration of Helsinki and its later amendments.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eGeneral demographic and clinical characteristics\u003c/h2\u003e \u003cp\u003eThe median age of the population studied was 70 [66\u0026ndash;75], and 43% were women, with no significant differences across groups. Median PSPRS scores were 26 [\u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] in PSP-P and 34 [\u003cspan additionalcitationids=\"CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] in PSP-RS, while UPDRS-III scores in PD were 20 [\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. PSP-RS were more cognitively impaired and presented a higher HY than the rest. No significant differences were observed in anxiety scores (HADS-A) across groups, whereas patients with PD, PSP-P and PSP-RS scored higher on depression (HADS-D) compared to CS. In one patient with PSP-RS, the diagnosis was pathologically confirmed. See Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of assessments by diagnostic groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCS\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePSP-P\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePSP-RS\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSignificant p-FDR values\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 [\u003cspan additionalcitationids=\"CR62 CR63 CR64 CR65 CR66 CR67 CR68 CR69 CR70\" citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 [64\u0026ndash;77]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69 [66\u0026ndash;76]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71 [68\u0026ndash;75]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex (women %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDisease duration (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMoCA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 [\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 [\u003cspan additionalcitationids=\"CR25 CR26 CR27\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 [\u003cspan additionalcitationids=\"CR25 CR26 CR27\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22 [\u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll groups: 0.021; CS vs. PSP-RS: 0.007; PD vs. PSP-RS: 0.077; PSP-P vs. PSP-RS: 0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHY\u0026thinsp;\u0026lt;\u0026thinsp;3 (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll groups: \u0026lt;0.001; PD vs. PSP-P: 0.047; PD vs. PSP-RS: \u0026lt;0.001; PSP-P vs. PSP-RS: \u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePSQI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.5 [2.5\u0026ndash;4.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 [7\u0026ndash;12.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 [5.5\u0026ndash;14]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll groups: 0.0002; PD vs. CS p\u0026thinsp;=\u0026thinsp;0.009; PSP-P vs. CS p\u0026thinsp;=\u0026thinsp;0.0002; PSP-RS vs. CS p\u0026thinsp;=\u0026thinsp;0.0002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHADS-A\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.5 [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 [3.5\u0026ndash;7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.5 [3\u0026ndash;9.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 [3.5\u0026ndash;10]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHADS-D\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 [0\u0026ndash;4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 [2.5\u0026ndash;7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 [3\u0026ndash;9.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 [5\u0026ndash;11.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll groups: 0.00035; PD vs. CS p\u0026thinsp;=\u0026thinsp;0.0079; PSP-P vs. CS p\u0026thinsp;=\u0026thinsp;0.0005; PSP-RS vs. CS p\u0026thinsp;=\u0026thinsp;0.00035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUPSIT percentile\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 [\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 [\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll groups: \u0026lt;0.001; CS vs. PD: \u0026lt;0.001; CS vs. PSP-P: 0.001; CS vs. PSP-RS: 0.004; PD vs. PSP-RS: 0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUPSIT\u0026thinsp;\u0026le;\u0026thinsp;15th percentile\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll groups: \u0026lt;0.001; CS vs. PD: \u0026lt;0.001; CS vs. PSP-P: \u0026lt;0.001; CS vs. PSP-RS: 0.014.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003efRBD\u0026thinsp;+\u0026thinsp;inRBD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e0%\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e35%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll groups: 0.004; CS vs. PD: \u0026lt;0.001; CS vs. PSP-P: 0.019; CS vs. PSP-RS: 0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOrthostatic hypotension\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll groups: 0.001; CS vs PD: 0.006; PD vs PSP-P: 0.006; PD vs PSP-RS: 0.098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSCOPA-AUT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 [\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 [\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 [\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 [\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll groups: \u0026lt;0.001; CS vs. PD: 0.004; CS vs. PSP-P: \u0026lt;0.001; CS vs. PSP-RS: 0.002; PD vs. PSP-P: 0.028; PD vs. PSP-RS: 0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNicturia severe\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e42%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll groups: 0.019; CS vs. PD: p 0.053; CS vs. PSP-P: p\u0026thinsp;=\u0026thinsp;0.019; CS vs. PSP-RS: p\u0026thinsp;=\u0026thinsp;0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTUHARS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 [0\u0026ndash;0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5 [0\u0026ndash;1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 [0\u0026ndash;1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 [0\u0026ndash;0.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cem\u003eCS: control subjects; fRBD: full REM sleep behaviour disorder; HADS: Hospital Anxiety and Depression Scale, -A: anxiety, -D: depression; HY: Hoehn and Yahr rating scale; inRBD: incomplete REM sleep behaviour disorder; MoCA: Montreal Cognitive assessment; NA: Not Applicable; p-FDR: p-values corrected by false discovery rate; PD: Parkinson disease; PSQI: Pittsburgh Sleep Quality Index; PSP-P: progressive supranuclear palsy, parkinsonian variant; PSP-RS: progressive supranuclear palsy, Richardson syndrome variant; SCOPA-AUT: Scales for Outcomes in Parkinson Disease\u0026ndash;Autonomic; TUHARS: Tottori University Hallucination Rating Scale; UPSIT: University of Pennsylvania Smell Identification Test.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eHyposmia\u003c/h3\u003e\n\u003cp\u003eUPSIT percentiles were lower in PD: 5 [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], PSP-P: 9 [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], PSP-RS: 11 [8\u0026ndash;18, compared with CS 25: [\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]; overall p-FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). PSP-RS performed better than PD (p-FDR\u0026thinsp;=\u0026thinsp;0.006), whereas PSP-P did not differ significantly from either PD or PSP-RS. The proportion of individuals equal or below the 15th percentile was 85% in PD, 75% in PSP-P, 60% in PSP-RS, and 15% in CS (\u003cb\u003eSuppl. Table\u0026nbsp;1\u003c/b\u003e). The agreement between subjective and UPSIT-defined hyposmia varied across groups (\u003cb\u003eSuppl. Table\u0026nbsp;1\u003c/b\u003e). CS showed the highest concordance (κ\u0026thinsp;=\u0026thinsp;0.46, p\u0026thinsp;=\u0026thinsp;0.007), followed by PSP-P (κ\u0026thinsp;=\u0026thinsp;0.37, p\u0026thinsp;=\u0026thinsp;0.035), whereas concordance was low and non-significant in PD (κ\u0026thinsp;=\u0026thinsp;0.08) and PSP-RS (κ\u0026thinsp;=\u0026thinsp;0.15). If subjective hyposmia alone had been considered, misclassification would have occurred in 10% of CS, 30% of PD and PSP-P, and 45% of PSP-RS cases.\u003c/p\u003e\n\u003ch3\u003eSleep disturbances\u003c/h3\u003e\n\u003cp\u003eThere were no significant differences in the use of sleep-related medications among PD, PSP-P and PSP-RS, including benzodiazepines or antipsychotics (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eMedication profile across diagnostic groups\u003c/b\u003e Use of antiparkinsonian and neuropsychiatric medications in each study group. Data are expressed as the number and percentage of patients receiving each drug class. Levodopa equivalent daily dose (LEDD) is presented as median [IQR]. Neuropsychiatric medications include benzodiazepines, antidepressants (not limited to those with sedative effects), and antipsychotics.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePSP-P\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePSP-RS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCS vs PD\u003c/p\u003e \u003cp\u003ep-FDR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCS vs PSP-P\u003c/p\u003e \u003cp\u003ep-FDR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCS vs PSP-RS\u003c/p\u003e \u003cp\u003ep-FDR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePD vs PSP-P\u003c/p\u003e \u003cp\u003ep-FDR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePD vs PSP-RS\u003c/p\u003e \u003cp\u003ep-FDR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003ePSP-P vs PSP-RS\u003c/p\u003e \u003cp\u003ep-FDR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eAll groups\u003c/p\u003e \u003cp\u003ep-FDR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLEDD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(mg/d)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e800\u003c/p\u003e \u003cp\u003e[700\u0026ndash;940]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e775\u003c/p\u003e \u003cp\u003e[600\u0026ndash;1100]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e850\u003c/p\u003e \u003cp\u003e[575\u0026ndash;1050]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.912\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.912\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.912\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBenzodiazepines\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.247\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.247\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.873\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.2475\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.2475\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.215\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAntidepressants n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (65%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.6312\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.033\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.024\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.0855\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.751\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e\u003cb\u003e0.020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAntipsychotics\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.6936\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.6936\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e\u003cb\u003e0.046\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003cem\u003eCS: control subjects; p-FDR: p-values adjusted for False Discovery Rate; PD: Parkinson\u0026rsquo;s disease; PSP: progressive supranuclear palsy; PSP-P: PSP-parkinsonism; PSP-RS: PSP-Richardson\u0026rsquo;s syndrome.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSymptoms compatible with \u003cem\u003efRBD\u003c/em\u003e were present in 50% of PD, but only in 20% of each group of PSP. In contrast, \u003cem\u003einRBD\u003c/em\u003e was present similarly in all patient groups (25% of PSP-P and 15% of PD and PSP-RS; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). When full and incomplete RBD were pooled, the prevalence differed significantly across groups (p-FDR\u0026thinsp;=\u0026thinsp;0.004), with higher frequencies in PD and PSP-P compared to CS (p-FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and 0.019, respectively). No significant differences were observed between PD, PSP-P and PSP-RS (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among participants with probable RBD, the parasomnia appeared after the motor symptoms of the disease more frequently in PSP than in PD (89% of PSP-P, 86% of PSP-RS, and 38% of PD), with a significant overall difference (p-no FDR\u0026thinsp;=\u0026thinsp;0.030) and pairwise comparisons showing significance for PSP-P vs. PD (p-no FDR\u0026thinsp;=\u0026thinsp;0.031) and a trend for PSP-RS vs. PD (p-no FDR\u0026thinsp;=\u0026thinsp;0.070), but no difference between PSP-P and PSP-RS (p-no FDR\u0026thinsp;=\u0026thinsp;1.000) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eExcessive daytime sleepiness was more frequent in PD, followed by PSP-P and PSP-RS, and was less common in CS, while RLS occurred in 35% of PD, 26% of PSP-RS, 5% of PSP-P, and 16% of CS, with no difference between groups. Further details are available in the \u003cb\u003eSupplementary Results\u003c/b\u003e \u0026amp; \u003cb\u003eSuppl. Figure\u0026nbsp;1\u0026ndash;2\u003c/b\u003e.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAutonomic symptoms\u003c/h2\u003e \u003cp\u003eAn abnormal orthostatic test was observed more frequently in PD (40%) than in CS (0%, p-FDR\u0026thinsp;=\u0026thinsp;0.006) and PSP-P (0%, p-FDR\u0026thinsp;=\u0026thinsp;0.006). Two PSP-RS, one was the neuropathologically confirmed, also showed abnormal results, both receiving high doses of dopaminergic agents (\u0026gt;\u0026thinsp;2g per day).\u003c/p\u003e \u003cp\u003eNocturia was commonly reported in PD, PSP-P and PSP-RS, being severe (\u0026ge;\u0026thinsp;3 voids/night) in 42% of PSP-RS and 35% in PSP-P and PD, compared to only 5% in CS.\u003c/p\u003e \u003cp\u003eSCOPA-AUT scores were highest in PSP-P (23 [\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]) and PSP-RS (23 [\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]), followed by PD (15 [\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]) and CS (8 [\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]; overall p-FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.001). PD, PSP-P and PSP-RS scored higher than CS (all p-FDR\u0026thinsp;\u0026le;\u0026thinsp;0.002), and both PSP groups scored higher than PD (p-FDR\u0026thinsp;=\u0026thinsp;0.024 and p-FDR\u0026thinsp;=\u0026thinsp;0.015), with no significant difference between them (p-FDR\u0026thinsp;=\u0026thinsp;0.808). Analysis of the individual domains showed that gastrointestinal, urinary and cardiovascular functions were significantly more impaired in PD, PSP-P and PSP-RS compared to CS. In the gastrointestinal domain, PSP-RS scored worse than PD, but this trend turned borderline significant after FDR correction (p-FDR\u0026thinsp;=\u0026thinsp;0.072). Pupillomotor dysfunction was significantly higher in PSP-P and PSP-RS compared with PD (p-FDR\u0026thinsp;=\u0026thinsp;0.034 \u0026amp; p-FDR\u0026thinsp;=\u0026thinsp;0.002, respectively) and to CS (p-FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No significant differences were observed in either the sexual or termoregulatory domains (\u003cb\u003eSuppl. Figure\u0026nbsp;3\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eHallucinations\u003c/h2\u003e \u003cp\u003eHallucinations (TUHARS) were infrequent across all diagnostic groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eDiscriminative clinical features\u003c/h2\u003e \u003cp\u003eUnivariate logistic regression analyses are summarized in \u003cb\u003eSuppl. Tables\u0026nbsp;2\u0026ndash;4\u003c/b\u003e and visually represented in the forest plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Lower UPSIT scores (OR\u0026thinsp;=\u0026thinsp;0.91, p-no FDR\u0026thinsp;=\u0026thinsp;0.032), orthostatic hypotension (OR\u0026thinsp;=\u0026thinsp;12.7, p-no FDR\u0026thinsp;=\u0026thinsp;0.003), \u003cem\u003efRBD\u003c/em\u003e (OR\u0026thinsp;=\u0026thinsp;4.0, p-no FDR\u0026thinsp;=\u0026thinsp;0.020) and premotor probable RBD (OR\u0026thinsp;=\u0026thinsp;11.2, p-no FDR\u0026thinsp;=\u0026thinsp;0.011) significantly discriminated PD from PSP. Specifically in the comparison between PD and PSP-P, \u003cem\u003efRBD\u003c/em\u003e (OR\u0026thinsp;=\u0026thinsp;4.0, p-no FDR\u0026thinsp;=\u0026thinsp;0.053) and premotor probable RBD (OR\u0026thinsp;=\u0026thinsp;12.8, p-no FDR\u0026thinsp;=\u0026thinsp;0.034) showed the strongest discriminative capacity, with AUC values of 0.65 and 0.75, respectively. In the comparison between PSP-P and PSP-RS, none of the syn-like features significantly discriminated between the two phenotypes.\u003c/p\u003e \u003cp\u003eA simple 3-item mini-score (\u003cem\u003efRBD\u003c/em\u003e, premotor probable RBD, UPSIT\u0026thinsp;\u0026le;\u0026thinsp;15th percentile; 0\u0026ndash;3 points) showed fair discrimination between PD and PSP-P (AUC\u0026thinsp;=\u0026thinsp;0.71, 95% CI 0.57\u0026ndash;0.86). Using a prespecified cut-off \u0026ge;\u0026thinsp;2 points yielded 50% sensitivity, 85% specificity, PPV 0.77 and NPV 0.63 (AUC\u0026thinsp;=\u0026thinsp;0.68, 95% CI 0.54\u0026ndash;0.81).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCSF biomarkers\u003c/h2\u003e \u003cp\u003eWe obtained CSF from 5 controls, 11 PD, 17 PSP-P, and 17 PSP-RS participants.\u003c/p\u003e \u003cp\u003eAll PD were positive results for asyn-SAA, followed by 24% of PSP-P and none of both PSP-RS and controls (PSP-P vs PD p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; PSP-P vs PSP-RS p\u0026thinsp;=\u0026thinsp;0.103). Among PSP-P, asyn-SAA positivity (4/17, 24%) was not associated with greater motor (PSPRS: 28 [\u003cspan additionalcitationids=\"CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] vs. 27 [\u003cspan additionalcitationids=\"CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]; p-FDR\u0026thinsp;=\u0026thinsp;0.69) or cognitive impairment (MoCA: 28 [\u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27 CR28\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] vs. 24 [\u003cspan additionalcitationids=\"CR23 CR24 CR25 CR26 CR27\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]; p-FDR\u0026thinsp;=\u0026thinsp;0.61), nor with significantly higher frequencies of hyposmia (100% vs. 62%; p-FDR\u0026thinsp;=\u0026thinsp;0.26), pooled probable RBD (75% vs. 31%; p-FDR\u0026thinsp;=\u0026thinsp;0.25), or orthostatic hypotension (0% in both groups), although subgroup sample sizes were small.\u003c/p\u003e \u003cp\u003eCSF-NfL levels differed significantly across groups (p-FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Median values were 832 [497\u0026ndash;870] pg/mL in CS, 880 [509\u0026ndash;1285] pg/mL in PD, 1046 [604\u0026ndash;1193] pg/mL in PSP-P, and 2269 [1699\u0026ndash;3479] pg/mL in PSP-RS. Pairwise comparisons showed higher NfL in PSP-RS compared with CS (p-FDR\u0026thinsp;=\u0026thinsp;0.039), PD (p-FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and PSP-P (p-FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas no significant differences were found between PD or PSP-P with CS. Within the PSP-P group, CSF NfL levels did not differ significantly between asyn-SAA\u0026ndash;negative (n\u0026thinsp;=\u0026thinsp;13; median 775 [599\u0026ndash;1193] pg/mL) and asyn-SAA\u0026ndash;positive cases (n\u0026thinsp;=\u0026thinsp;4; median 1088 [893\u0026ndash;1230] pg/mL; p-FDR\u0026thinsp;=\u0026thinsp;0.57), although the number of patients was small.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePathological case\u003c/h2\u003e \u003cp\u003eOne of the participants died and was a brain donor. The disease began at age 63 with early falls, difficulty looking downward, and reduced facial expressiveness. At the time of evaluation, the patient exhibited supranuclear vertical gaze palsy (both upward and downward), moderate bradykinesia, resting tremor of the left arm, unsteady gait, and impaired postural reflexes, fulfilling clinical criteria for probable PSP-Richardson\u0026rsquo;s syndrome. The UPSIT score corresponded to the 16th percentile, the orthostatic blood pressure test was abnormal, and a probable \u003cem\u003einRBD\u003c/em\u003e pattern was identified. Altogether, this profile was consistent with syn-like clinical features, with olfactory performance lying close to the predefined hyposmia cut-off (see Methods). However, CSF asyn-SAA was negative, as were Alzheimer\u0026rsquo;s biomarkers (beta amyloid 890 pg/ml, tau 256 pg/ml, pTau 30 pg/ml). CSF-NfL were increased (3479 pg/ml).\u003c/p\u003e \u003cp\u003eNeuropathological examination revealed a predominant 4-repeat tauopathy consistent with PSP (Kovacs stage 5/6 and Williams stage 10/12). Tau pathology was abundant in the ventral medullary tegmentum, including the gigantocellular nucleus, and in the pontine tegmentum, involving the locus coeruleus and the subcoeruleus nucleus. These regions, relevant for syn-like features afforded by this patient, also showed globose neurofibrillary tangles, neurites, and pretangles. These neuropathological features exceeded those from two other PSP cases from the Neurological Tissue Bank used for comparison purposes. In keeping with negative asyn-SAA, no α-synuclein was identified in general, including specific assessment of the medulla and the pons. TDP-43 pathology was absent too. Alzheimer\u0026rsquo;s disease\u0026ndash;related changes (A1B1C0) and cerebrovascular pathology were low-grade and mild, and thus deemed unlikely to account for clinical features.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, non-motor features classically linked to α-synucleinopathies followed a gradient across PD \u0026gt; PSP-P \u0026gt; PSP-RS, with a higher-than-expected frequency in PSP, particularly in PSP-P. While hyposmia, probable RBD, and autonomic symptoms were common in PD, PSP-P and PSP-RS, the timing and pattern of these manifestations retained diagnostic value: premotor RBD and orthostatic hypotension were mainly associated with PD, whereas in patients with PSP (both, PSP-P and PSP-RS), probable RBD typically appeared after motor onset and\u0026nbsp;SCOPA-AUT scores were higher, mainly due to greater impairment in pupillomotor domain.\u0026nbsp;At the biomarker level, despite a proportion of asyn-SAA positive PSP-P cases, the results still clearly distinguished PSP-P from PD, whereas CSF-NfL did not differentiate between these two groups. Finally, while PSP-P group featured a proportion of patients with syn-like clinical features and part of cases with positive asyn-SAA, clinical and biological synucleinopathy did not match, suggesting that underlying asyn co-pathology may not account (at least not in all instances) for syn-like symptoms in PSP-P.\u003c/p\u003e\n\u003cp\u003eRegarding hyposmia, early clinical series suggested it was absent or rare in PSP,\u003csup\u003e4,36–39\u003c/sup\u003e reinforcing its use as a marker of synucleinopathies. However, we have encountered hyposmia in 67.5% of our PSP patients, consistent with recent reports showing a higher-than-expected frequency, sometimes approaching that of PD,\u003csup\u003e40,41\u003c/sup\u003e although none specifically addressed PSP-P. Neuropathological data provide plausible explanations for the occurrence of hyposmia in PSP. Tau pathology has been described in the rhinencephalon of PSP patients,\u003csup\u003e39,42\u003c/sup\u003e suggesting a direct contribution to olfactory impairment, yet hyposmia was not observed in all patients with involvement of these regions.\u003csup\u003e39\u003c/sup\u003e Alternatively, olfactory loss in PSP may reflect concomitant Lewy body copathology, as higher α-synuclein burden has been correlated with lower UPSIT scores.\u003csup\u003e42\u003c/sup\u003e In contrast to PD, where early α-synuclein involvement of the olfactory bulb is well established,\u003csup\u003e43\u003c/sup\u003e PSP does not typically show this pattern, supporting a more central mechanism possibly related to brainstem or rhinencephalic integrative structures.\u003csup\u003e39,42,44\u003c/sup\u003e Importantly, in our cohort, subjective hyposmia and UPSIT-defined hyposmia correlated only moderately in PSP-P and controls, but not in PSP-RS or PD. This discordance suggests that relying solely on subjective complaints risks underestimating the true prevalence of olfactory loss.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs for RBD,\u0026nbsp;in PSP\u0026nbsp;polysomnographic studies have reported variable prevalence (8% to 35%).\u003csup\u003e45–48\u003c/sup\u003e Converging evidence indicates that RBD emerges when key regions such as the locus coeruleus/subcoeruleus complex, the ventromedial medulla or the pedunculopontine area are affected.\u003csup\u003e49–52\u003c/sup\u003e Supporting this, our group described a pathologically confirmed PSP case with RBD, showing tau pathology in these regions.\u003csup\u003e53\u003c/sup\u003e Altogether, these observations suggest that dysfunction of specific brainstem nuclei, rather than the protein aggregate type, underlies the pathophysiology of RBD.\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA novel aspect of our study is that, beyond assessing probable RBD across PSP phenotypes, we found that it tended to precede motor onset in PD, whereas it appeared after motor onset in PSP. Logistic univariate regression models confirmed this pattern, showing that premotor RBD strongly discriminated PD from PSP and specifically PD from PSP-P.\u0026nbsp;This temporal relationship with the motor symptoms likely reflects the distinct neuroanatomical progression of pathology in both diseases: whereas α-synuclein pathology in PD seems to follow a caudal-to-rostral trajectory involving early degeneration of the pontomedullary REM-atonia network,\u003csup\u003e43\u003c/sup\u003e tau pathology in PSP originates in the basal ganglia and midbrain, affecting these lower brainstem structures in later stages.\u003csup\u003e54\u003c/sup\u003e Moreover, RBD manifestations in PSP were often subtler in our study, a finding in agreement with a previous work,\u003csup\u003e45\u003c/sup\u003e that\u0026nbsp;reported that none of their PSP patients exhibited overt dream-enactment behaviors despite the presence of REM sleep without atonia in video-PSG. They speculated that more severe motor and cognitive impairment in PSP might mask RBD manifestations, and that PSP patients may experience less vivid or violent dream content compared to PD.\u003c/p\u003e\n\u003cp\u003eRegarding dysautonomic function, both PSP variants showed significantly higher SCOPA-AUT scores than PD, in line with recent studies.\u003csup\u003e55,56\u003c/sup\u003e Pupilomotor impairment, which may manifest with photophobia or blurred vision, is consistently more pronounced in PSP than in PD, and these visual complaints can emerge several years before the clinical diagnosis of parkinsonism.\u003csup\u003e57\u003c/sup\u003e Studies using pupillography and chromatic pupillometry show smaller dark-adapted pupils and slower light-reflex responses in PSP.\u003csup\u003e58,59\u003c/sup\u003e This has been attributed to the more extensive tau-mediated degeneration of midbrain pupillary control centres, especially the pretectal Edinger-Westphal complex and adjacent autonomic pathways.\u003csup\u003e60\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eReports on orthostatic hypotension in PSP have been inconsistent. In our cohort, OH was absent in PSP-P and rare in PSP-RS, in contrast with 40% prevalence in PD. These findings are aligned with previous studies showing low prevalence of neurogenic OH in PSP,\u003csup\u003e55,56,61,62\u003c/sup\u003e although higher frequencies have been reported by other authors.\u003csup\u003e63,64\u003c/sup\u003e These discrepancies likely reflect methodological differences such as diagnostic criteria, exclusion of comorbidities, and dopaminergic medication use.\u003csup\u003e65\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe prevalence of hallucinations was low across all groups. In PSP, hallucinations are generally uncommon but not exceptional as have been shown in autopsy-based data\u003csup\u003e10,66\u003c/sup\u003e and in clinical studies too.\u003csup\u003e67\u003c/sup\u003e In PD, a higher frequency would usually be expected; in our cohort, however, the low rate is plausibly explained by the exclusion of individuals with significant cognitive impairment, given the well-described association between cognitive decline and hallucinations in synucleinopathies.\u003csup\u003e68,69\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our cohort, CSF-NfL was higher in PSP-RS than in PSP-P and PD, which showed overlapping values. This is consistent with extensive literature demonstratig that PSP-P constitutes a lesser aggressive phenotype with slower progression and longer survival.\u003csup\u003e70,71\u003c/sup\u003e Regarding\u0026nbsp;asyn-SAA, both PSP-RS and PSP-P showed significantly lower positivity than PD, although occasional positivity in PSP-P underscores that this assay cannot be used in isolation to distinguish both entities. In this setting, 4R-tau biomarkers, like tau-PET or tau-SAA would be of valuable interest.\u003c/p\u003e\n\u003cp\u003eThis study is not without limitations. First, the sample size was modest, specifically regarding CSF, not available for all cases, and when stratifying by phenotype, limiting statistical power for subgroup analyses. Furthermore, we only have neuropathological confirmation of one case and specific 4R-tau biomarkers were not available. Hence, caution is required when interpretating our results overall, and the non-significant trends, in particular. Second,\u0026nbsp;RBD was diagnosed clinically rather than by video-PSG, which remains the gold standard. However, structured interviews by an experienced sleep neurologist incorporating information from both the patient and the bed partner and clinically excluding confounding disorders (e.g., severe sleep apnea or restless legs syndrome) has been proven to be specific.\u003csup\u003e72\u003c/sup\u003e Third, autonomic dysfunction was assessed by questionnaire and orthostatic testing, but no additional evaluations were performed.\u0026nbsp;Fourth, olfactory assessment was limited to the UPSIT, which, while standardized, can be influenced by cultural and cognitive status.\u003c/p\u003e\n\u003cp\u003eDespite these limitations, this study has several notable strengths. The inclusion of 20 patients per PSP phenotype represents a relatively large and well-balanced cohort for a rare disorder. \u0026nbsp;All participants underwent detailed and harmonized clinical characterization, with minimal missing data. Furthermore, the parallel assessment of sleep, olfactory, and autonomic domains, together with CSF biomarker in a subset of the cohort, provides a comprehensive multidimensional view of PSP-P and PSP-RS that is rarely achieved in single-center studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, our findings reveal that non-motor features traditionally linked to α-synucleinopathies are also common in PSP, particularly in the PSP-P variant, which also has greater proportion of biologically defined synucleinopathy. However, syn-like clinical features did not completely match with biologically defined synucleinopathy, suggesting overlapping yet distinct pathogenic mechanisms. Hence, syn-like clinical features might be determined by synuclein co-pathology in some cases, whereas in some others it could be the topographical involvement of specific brain regions by primary tauopathy what might account for these symptoms. Further longitudinal studies including 4R-tau wet or imaging markers, objective dysautonomia and sleep assessments, and more pathologically confirmed cases, are warranted to confirm or not our observations suggesting that not only concomitant synucleinopathy, but also strategic regional tau deposition, underlie the phenotypic overlap between PD and PSP-P.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to the inclusion of confidential and sensitive patient information, but they are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS:\u0026nbsp;\u003c/strong\u003eWe thank all patients that willfully participated in the Barcelona PSP Registry. This study was funded by “La Marató de TV3” Foundation. The funder played no role in the study design, data collection, analysis, interpretation of data, or writing of the manuscript. We are indebted to the Biobanc-Hospital Clinic-FRCB-IDIBAPS for samples and data procurement. MF is funded by Institut de neurociències de la Universitat de Barcelona, Maria de Maeztu\u0026nbsp;CEX2021-001159-M / financiada por MICIU/AEI / 10.13039/501100011033.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' Roles:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eList all authors along with a clarification of role(s): e.g. design (D), execution (E), analysis (A), writing (W), editing of final version of the manuscript (R).\u003c/p\u003e\n\u003cp\u003eCP: D, E, A, W, R\u003c/p\u003e\n\u003cp\u003eAM: E, A, W, R\u003c/p\u003e\n\u003cp\u003eAC: E (research nurse coordinator), R\u003c/p\u003e\n\u003cp\u003eMF, LdM, JPM: E, A (NfL analysis), R\u003c/p\u003e\n\u003cp\u003eRRG, LN: E, A (asyn-SAA analysis), R\u003c/p\u003e\n\u003cp\u003eMJM, EM, ASG, APS, AG, FV, ET, NC, SJ, CPS, TD, AL, CB: E, R (Expert opinion, patient recruitment)\u003c/p\u003e\n\u003cp\u003eIA, LMP: A (Postmortem analysis), R\u003c/p\u003e\n\u003cp\u003eJS: D, A, R (principal investigator)\u003c/p\u003e\n\u003cp\u003eYC: D, A, R (principal investigator)\u003c/p\u003e\n\u003cp\u003eBarcelona PSP-Registry CONSORTIUM: patient Recruitment\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Disclosures of all authors (for the preceding 12 months)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no financial or non-financial competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eGoedert, M. 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We studied 80 subjects: 20 PSP-P, 20 PSP-Richardson-syndrome (PSP-RS), 20 PD, and 20 controls (CS). Procedures included specific smell-testing, structured interview by a sleep specialist, orthostatic-stress test, specific dysautonomia scale, CSF-α-synuclein seed-amplification-assay (asyn-SAA) and neurofilament-levels (NfL). Frequency of syn-like symptoms was low in CS+PSP-RS, intermediate in PSP-P, and high in PD. Premotor probable-RBD and orthostatic hypotension favoured PD, whereas probable-RBD after motor onset and higher pupillomotor dysautonomia scale scores predominated in PSP groups. NfL peaked in PSP-RS, not differing among PSP-P, PD and CS. asyn-SAA was 100% positive in PD, 100% negative in CS+PSP-RS, and positive in 24% PSP-P. Not all clinically-syn-like PSP-P cases were asyn-SAA positive, and vice versa. In summary, while partly overlapping with PD (including mild neurodegeneration as per NfL), syn-like symptoms do not always match biological synucleinopathy in PSP-P.\u003c/p\u003e","manuscriptTitle":"Synucleinopathy-like Clinical Features and Biologically Defined Synucleinopathy in Psp-parkinsonism: An Imperfect Match","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-16 08:56:24","doi":"10.21203/rs.3.rs-8470662/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-09T11:08:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-01T23:11:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-21T01:52:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"319786306285195222551472391647271088220","date":"2026-01-20T09:54:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"256033625321519513787271233787370746648","date":"2026-01-19T23:05:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-12T09:39:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-02T15:34:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-01T05:37:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Parkinson's Disease","date":"2025-12-29T07:52:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-parkinsons-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjparkd","sideBox":"Learn more about [npj Parkinson's Disease](http://www.nature.com/npjparkd/)","snPcode":"41531","submissionUrl":"https://submission.springernature.com/new-submission/41531/3","title":"npj Parkinson's Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"52d60082-99cf-4b2d-88bc-2cd92864c286","owner":[],"postedDate":"January 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":61112145,"name":"Health sciences/Diseases"},{"id":61112146,"name":"Health sciences/Neurology"},{"id":61112147,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-05-06T07:54:33+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-16 08:56:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8470662","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8470662","identity":"rs-8470662","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}