Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy neurodegenerative disorder that presents with parkinsonism features and is often indistinguishable from Parkinson disease (PD) in the early stages. The potential of plasma levels of phosphorylated tau (pTau) to differentiate PSP from PD remains unclear. The aim of this study was to identify noninvasive, cost-effective alternatives to tau PET imaging for differentiating PSP from PD. We measured plasma biomarkers, including pTau species (pTau217, pTau181, and pTau231), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), in 2 cohorts recruited from multiple centers across Taiwan. The exploratory cohort included patients with PSP and corticobasal degeneration (CBS) who underwent 18F-florzolotau PET to confirm underlying tau pathology. All participants with PSP and CBS in this cohort were confirmed negative for amyloid pathology based on either amyloid PET imaging or the plasma Aβ42/Aβ40 ratio. An independent validation cohort, consisting of clinically diagnosed PSP patients without 18F-florzolotau PET imaging, was also recruited. A total of 275 participants were included in this study: 195 participants in the exploratory cohort (46 controls, 64 patients with PD and normal cognition, 18 patients with CBS, and 67 patients with PSP) and 80 patients with PSP in the validation cohort. Patients with PSP and CBS had higher levels of pTau217, pTau181, pTau231, and NfL compared with the other groups (all p < 0.05). In the PSP exploratory cohort, plasma levels of pTau217 (r = -0.270, p = 0.031), NfL (r = -0.363, p = 0.003), and GFAP (r = -0.264, p = 0.035) negatively correlated with cognitive performance, while only NfL levels were associated with PSP Rating Scale scores (r = 0.303, p = 0.023). Plasma pTau217 levels positively correlated with cortical tau burden in CBS but negatively correlated with tau tracer uptake in the subthalamic nucleus on 18F-florzolotau PET in PSP. The combination of pTau217 and NfL with the midbrain-to-pons ratio on brain MRI showed satisfactory performance in differentiating PSP from PD (area under the curve [AUC] 0.946, p < 0.0001), which was comparable to 18F-florzolotau PET (AUC 0.870, p = 0.001) and confirmed in the validation cohort (AUC 0.825, p < 0.0001). The combination of plasma pTau217 and NfL with brain MRI represents a noninvasive and clinically feasible strategy for distinguishing PSP from PD.

ERBB4 colocalizes with phosphorylated tau aggregates in multiple tauopathies.

Protein aggregation and transmission are hallmarks of neurodegenerative diseases. Praja1 E3 ubiquitin ligase has been shown to suppress the aggregation of causative proteins in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Parkinson's disease, Huntington's disease, and spinocerebellar degeneration, which include transactivation response DNA-binding protein of 43 kDa, fused in sarcoma, superoxide dismutase 1, α-synuclein, huntingtin, and ataxin-3. Aoki etal. demonstrated that Praja1 ubiquitinates and degrades tau, a key molecule in tauopathies such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal syndrome, furthering our understanding of the role of Praja1 in neurodegenerative diseases and potential therapeutic approaches.

ABSTRACTBackgroundHyposmia is present in most patients with Parkinson's disease (PD), whereas olfaction is usually preserved in its diagnostic mimics. To address the limited evidence from smaller studies, we conducted a meta‐analysis on the diagnostic accuracy of olfactory testing in differentiating PD from clinical look‐alikes.MethodsA systematic search was performed in PubMed and Web of Science according to the PRISMA guidelines. Studies describing results of validated smell tests in PD patients and at least one differential diagnosis were included. The risk of bias and applicability was assessed with the QUADAS‐2 tool. For data synthesis, a hierarchical regression model was employed.ResultsOf 787 publications, 23 studies describing 1957 PD patients, 462 patients with atypical parkinsonian disorders, 239 patients with essential tremor, and 43 patients with secondary parkinsonism were included. The meta‐analysis demonstrated a sensitivity of 79% (95% confidence interval [CI]: 72%–84%) and a specificity of 81% (95% CI: 73%–86%) for olfactory dysfunction to differentiate PD from all other disorders combined. Additional analyses showed consistent sensitivities across sub‐analyses, with lowest specificities for the distinction from progressive supranuclear palsy, 64% (95% CI: 55%–72%), and highest from essential tremor, 92% (95% CI: 84%–96%).ConclusionOur findings indicate that olfactory testing shows moderate to good diagnostic accuracy in differentiating PD from its main differential diagnoses. While results of olfactory testing alone are insufficient for a definite distinction of PD from non‐PD parkinsonism, it represents an easy‐to‐use and inexpensive test that may be used in combination with other diagnostic tools.

Neuroinflammation is increasingly recognized as a key driver of progressive supranuclear palsy (PSP), but the role of blood inflammatory markers remains unrevealed. This prospective cohort study aimed to characterize blood inflammatory protein profiles in PSP and to assess their associations with clinical severity, longitudinal progression, blood-based neurodegeneration markers, and brain morphometric changes. We enrolled 71 probable PSP patients and 30 age-matched healthy controls. Plasma concentrations of 39 inflammatory proteins were measured using a proximity extension assay. Data on clinical assessments, volumetric MRI, and blood biomarkers, including neurofilament light chain (NfL), phosphorylated tau 231, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and glial fibrillary acidic protein, were obtained. Follow-up clinical assessments were available for 56 patients at 6 months and 45 at 12 months. Principal component (PC) analysis identified three components explaining 55.6% of the variance. All PC scores were elevated in the PSP group compared to controls. PC1, mainly driven by interleukin (IL)-7, vascular endothelial growth factor A, and pro-epidermal growth factor, was associated with greater clinical severity, higher sTREM2 levels, and more pronounced atrophy in the cerebellum and limbic areas. PC3, mainly driven by IL-6, C-X-C motif chemokine 9, and oncostatin-M, was associated with greater clinical severity and faster disease progression, higher NfL levels, and more extensive atrophy in the frontoparietal regions and caudate nucleus. PC2 showed no associations with baseline and longitudinal outcomes. These observations suggest that blood inflammatory proteins reflect the neurodegenerative processes underlying PSP and serve as prognostic biomarkers.

BackgroundProgressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease characterized by movement, balance, speech, and eye movement difficulties. PSP is a form of four‐repeat tauopathy, involving the abnormal accumulation of tau in the brain. This accumulation leads to neuronal loss, particularly in the brainstem. Identifying robust biomarkers for disease progression is critical for minimizing the sample size in clinical trials. Advanced MRI‐based methods, such as regional volumetric and diffusion MRI (dMRI) processing and analyses, offer promising tools to detect subtle changes in brain structure. These methods allow for the analysis of both regional brain atrophy and microstructural changes, enabling insights into disease progression as well as enable the rapid evaluation of novel therapeutics in clinical trials.MethodsMRI data from PSP patients and healthy controls were acquired from the 4‐Repeat Tau Neuroimaging Initiative (4RTNI) and Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI). Fully‐automated image processing was performed using the PIANO™ software platform. Regional analysis focused on brain regions with significant atrophy or microstructural changes. Sample size calculations for clinical trials were performed to estimate the number of participants needed to detect a reduction in observed changes.ResultsOver 12 months, PSP patients exhibited up to 4% volume loss in key brain regions, such as the superior cerebellar peduncles, pallidum, midbrain, and brainstem (Figure 1), and statistically significant microstructural changes in RD and FW in white and gray matter regions (Figure 2). Sample size estimates revealed that fewer than 50 participants per arm were required to detect 60% slowing of changes in the most affected regions. In comparison, alternative methods, such as FreeSurfer and MRPI, required significantly larger sample sizes. The analysis also demonstrated 5‐10% increases in dMRI metrics over 12 months in PSP patients, compared to smaller changes in controls.ConclusionThe integration of advanced MRI processing techniques, including volumetric and dMRI analyses, enhances sensitivity to brain changes in PSP, significantly reducing sample size requirements for clinical trials. These findings underscore the importance of selecting robust imaging biomarkers and analysis methods to improve trial efficiency and accelerate therapeutic development for PSP.

ObjectivesThis study aimed to investigate four plasma markers, pTau231, sTREM2, neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP), in relation to disease severity in a Korean cohort of progressive supranuclear palsy (PSP).MethodsBaseline data from patients with probable PSP enrolled in the SCANPSP cohort (NCT05579301) were compared with those of age-matched healthy controls (HC). Four plasma markers measured using the Simoa method, clinical findings, and volumetric 3 T MRI were investigated.ResultsThis study included 68 patients with PSP and 30 HC. Group level difference were found in NFL, correlating with the PSP-rating scale (r = 0.48, p = 2.0·10–4) and global cognitive scores (r = −0.34, p = 0.0061 for Mini-Mental Status Exam: r = −0.32, p = 0.0088 for Montreal Cognitive Assessment). Intercorrelations between NFL, pTau231, and GFAP were observed in patients with PSP but no intercorrelations in HC. The combination of pTau231, NFL, and GFAP yielded the highest ability to distinguish the PSP-Richarson syndrome (PSP-RS) from the PSP-subcortical, with an area under the curve of 0.80. The gray matter voxel-wise correlation of whole patient data showed that NFL correlated with third ventricle enlargement and frontal/cingulate atrophy, whereas sTREM2 correlated with third ventricle and thalamic volumes. White matter analyses revealed that the supplementary motor area and vermis correlated with NFL in whole PSP. In PSP-RS group, the superior frontal gyrus was associated with NFL, and the cerebellar crus with sTREM2.ConclusionThis study demonstrated the feasibility of using four plasma markers simultaneously to determine PSP disease severity. To verify these findings, longitudinal analyses are necessary.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-025-13570-7.

BackgroundFrontotemporal lobar degeneration (FTLD) includes behavioral variant frontotemporal dementia (bvFTD), nonfluent and semantic variants of primary progressive aphasia (nfvPPA, svPPA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia associated with motor neuron disease (FTD‐MND). These syndromes are associated with prolonged time to diagnosis, impacting patient care and family outcomes. While diagnostic timelines have been studied in other regions, data from Latin America remain limited. Addressing this gap is essential to identify barriers and improve timeliness of diagnosis and treatment strategies.MethodWe analyzed 415 cases (mean age 66.5 ± 8.2 years) from the RedLat consortium (2021–2024): bvFTD (n = 232, 55.9%), svPPA (n = 68, 16.4%), nfvPPA (n = 33, 8%), non‐specified PPA (nsPPA; n = 13, 3.1%), PSP (n = 32, 7.7%), CBS (n = 22, 5.3%), FTD‐MND (n = 7, 1.7%), and non‐specified FTD (n = 8, 1.9%). Time to diagnosis was defined as the interval from first reported symptom (TDFRS) and first FTLD‐criteria symptom (TDFCS) to diagnosis. Clinical and sociodemographic factors influencing these timelines were also assessed.ResultDiagnostic timelines varied substantially. The most prevalent phenotype, bvFTD, had a mean (±SD) TDFRS of 3.54 ± 3.61 years and TDFCS of 3.09 ± 2.76 years. In contrast, svPPA (TDFRS = 3.47 ± 3.56; TDFCS = 3.08 ± 2.73) and PSP (TDFRS = 3.00 ± 2.64; TDFCS = 2.68 ± 1.94) showed similar durations. FTD‐MND exhibited the shortest timeline, with a mean duration of 1.29 ± 1.38 years for both TDFRS and TDFCS. Younger age at onset and lower education levels were associated with longer diagnostic timelines.ConclusionThis study highlights substantial variability in diagnostic timelines across FTLD phenotypes in Latin America. The longest timelines were seen for bvFTD, while FTD‐MND had the shortest. Younger patients and those with lower education faced greater challenges in obtaining timely diagnoses, suggesting sociodemographic disparities. These findings emphasize the need for targeted interventions, including increased clinical awareness, improved access to specialized care, and strategies to address disparities, optimizing the diagnostic process and outcomes for patients and families.

BackgroundBehavioral variant frontotemporal dementia (bvFTD) is characterized by neuropsychiatric symptoms (NPS) and personality changes that lead to functional decline and caregiver distress. There are currently no FDA‐approved pharmacotherapies for NPS in bvFTD, and existing medications, typically repurposed psychiatric and Alzheimer's agents, have limited efficacy in bvFTD. A more nuanced understanding of NPS in bvFTD is needed to inform individualized intervention. The present study uses network analysis to model NPS in bvFTD at initial clinic visit.MethodBvFTD patients were selected from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS). Patients with other FTDs or related syndromes (e.g., corticobasal degeneration, progressive supranuclear palsy, primary progressive aphasia, amyotrophic lateral sclerosis, Alzheimer's disease) were excluded. The final sample (n = 1066) consisted of predominantly non‐Hispanic white (NHW=88.6%, HW=3.2%, NH Black=2.1%, HB = .2%, other=6%,), well‐educated (Med=15.2[3.14]) older adults (Mage=62.7[9.66]; 38.3% female). The NPS network consisted of 12 Neuropsychiatric Inventory Questionnaire (NPI‐Q) items: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, appetite/eating problems. The eLasso method was used for network estimation, where “nodes” represent binary NPI‐Q items (e.g., symptom absent=0, symptom present=1) and “edges” represent their pairwise dependency. Node strength was calculated to determine relative importance of each NPI‐Q item to overall network connectivity.ResultMost of the sample met criteria for dementia (94.5%; mild cognitive impairment=5.5%). The most frequently endorsed symptom was apathy/indifference (79.01% endorsed) followed by disinhibition (67.70%). The NPI‐Q network (M = .197) consisted of positive edges, the strongest of which connected items within similar symptom domains. Four symptom clusters were identified: 1) hallucinations and delusions; 2) agitation/aggression and irritability/lability; 3) elation and disinhibition; 4) depression/dysphoria and anxiety; 5) apathy/indifference, appetite/eating problems, motor disturbance; 6) nighttime behaviors. Irritability/lability and agitation/aggression appeared to have highest node strength; however, centrality values were not stable and should be interpreted with caution.ConclusionNPS in bvFTD are highly interconnected—endorsing one NPS increases the likelihood of endorsing other NPS. Interventions targeting irritability and agitation may decrease symptom connectivity and “contagion”. Larger samples are needed to ensure stable centrality values and confirm network features. Findings may inform clinical presentations and management of NPS in bvFTD.

BackgroundImmediate improvements in subjective and objective symptoms can sometimes be observed following the administration of adipose‐derived mesenchymal stem cells (ADSCs). This rapid improvement was surprising, as we had assumed that regenerative medicine would require several days or more to show effects. Therefore, we measured grip strength and cholinesterase values before and after treatment. ADSCs have gained attention in regenerative medicine due to their multipotent nature and potential therapeutic effects.MethodWe conducted a prospective observational study on 21 patients who received ADSC treatment. Informed consent was obtained from all participants. Serum cholinesterase levels and grip strength were measured immediately before and after ADSC administration. Grip strength was measured on the non‐infusion side, maintaining the same posture for both pre‐ and post‐treatment measurements.ResultThe study included patients with various conditions: Parkinson's disease (PD, n=9), Amyotrophic Lateral Sclerosis (ALS, n=4), Alzheimer's disease (n=2), Chronic Obstructive Pulmonary Disease (COPD, n=4), and Progressive Supranuclear Palsy (PSP, n=1). The mean age was 67.5 years (range: 53‐81), with 14 males and 7 females. A paired samples t‐test revealed a statistically significant decrease in cholinesterase levels after ADSC administration (mean difference: ‐21.905 U/L, p < 0.001). Although not statistically significant, there was a trend towards improvement in grip strength (mean difference: 1.0619 kg, p = 0.119).ConclusionOur findings demonstrate a significant immediate decrease in serum cholinesterase levels following ADSC administration. The observed decrease in cholinesterase levels might indicate an enhancement of acetylcholine activity, potentially explaining the trend towards improved grip strength. The immediate effects observed in this study are intriguing, as they suggest that ADSCs may have rapid neuromodulatory effects beyond their known regenerative properties. Previous studies have shown that ADSCs can differentiate into various cell types, including neural cells, and secrete neurotrophic factors. The trend towards improved grip strength, although not statistically significant, is noteworthy. Grip strength is a reliable indicator of overall muscle strength and has been associated with various health outcomes. The potential improvement in grip strength immediately after ADSC administration warrants further investigation, as it could have implications for patients with neuromuscular disorders.

BackgroundProgressive Supranuclear Palsy (PSP) is a rapidly progressing 4‐repeat tauopathy, presenting with clinically heterogeneous phenotypes. Currently, diagnoses are based solely on clinical criteria but reliable diagnostic classification remains particularly challenging at early stages. 18F‐PI‐2620 tau‐PET is an evolving neuroimaging biomarker to capture 4‐repeat tau (4RT) deposits in vivo with clear diagnostic potential in research settings. To determine the added clinical value of 18F‐PI‐2620 tau‐PET in the diagnostic workup of PSP, we evaluated whether 18F‐PI‐2620‐assessed 4RT positivity (i.e. using the basal ganglia as a target readout) predicts subsequent increases of diagnostic certainty for PSP, indicative of 4RT pathology driving clinical progression.MethodWe collected monocentric longitudinal data at the LMU Hospital in Munich, from a non‐randomized prospective cohort study between October 2018 and December 2024. Data collection included pre‐PET visits with routine clinical classification following the MDS criteria. In addition, we performed 18F‐PI‐2620 tau‐PET with dichotomous visual read assessments of 4RT pathology by an expert reader and collected clinical follow‐up data or autopsy information.Results342 patients with a pre‐PET differential diagnosis of PSP were referred to 18F‐PI‐2620 tau‐PET in clinical routine. Of those, 200 patients (61.5% male, mean±sd age 69.2±8.3 years) had a post‐PET clinical follow‐up between 12‐24 months (mean±sd 17.1±4.2 months). 137 patients (68.5%) were rated 4RT‐positive at baseline (Figure 1). The distribution of certainty of PSP diagnosis at baseline and at follow‐up is displayed in Figure 2 (A&B: all PSP phenotypes; C&D: PSP‐Richardson Syndrome [RS]; E&F: variant PSP subtypes). Change to a non‐PSP diagnosis at follow‐up occurred in 23.5%, identified by a negative baseline tau‐PET in 95.5%. In contrast, 79% of tau‐PET‐positive patients with suggestive PSP progressed to a higher diagnostic certainty, 3% had histopathological confirmation of PSP diagnosis, 13% remained suggestive PSP, and 5% received a non‐PSP diagnosis at follow‐up.Conclusion18F‐PI‐2620 tau‐PET can successfully identify patients that progress along expected 4RT clinical spectra. This supports 18F‐PI‐2620 tau‐PET as a 4RT biomarker, with the potential to facilitate early biomarker‐based diagnosis when clinical criteria may still lack sensitivity and specificity. This development can be transformative for clinical decision making, pre‐symptomatic identification of PSP and stratifying patients for disease modifying clinical trials.

Brain segmentation using structural MRI is effective for identifying regional atrophy in Parkinsonian syndromes. However, clinical validation of the automated deep learning-based brainstem segmentation model has been limited. To develop and validate a two-step deep learning algorithm for automatic segmentation of brainstem substructures and classifying Parkinsonian syndromes using derived volumetric measurements. Retrospective. The internal dataset comprised 300 normal cognition (NC) subjects (171 females) for segmentation and 513 subjects (265 males) for classification (207 NC, 52 progressive supranuclear palsy [PSP], 65 multiple system atrophy-cerebellar variant [MSA-C], and 189 Parkinson's disease [PD]). The external dataset comprised 82 subjects (43 males; 24 PSP, 28 MSA-C, and 30 PD). 3D gradient-echo T1-weighted sequence at 3 T. Segmentation performance was evaluated with the Dice Similarity Coefficient (DSC) by comparing model outputs against manual labels. For classification, regional brain volumes from the segmentations were used as input features for multi-class classification with support vector machine (SVM), random forest, and XGBoost models, evaluated by area under the receiver operating characteristic curve (AUROC). Five-fold cross-validation was used for internal validation and tested on an external dataset. Three radiologists analyzed an external dataset with and without the model, with a one-month washout period between sessions. For the segmentation volume, differences between groups were assessed using Student's t-test or Mann-Whitney U test. Classification performance was evaluated using a one-vs-rest approach with macro-averaging across classes. Brainstem segmentation DSC scores were 0.969 (internal) and 0.996 (external) compared to the ground-truth masks. Using regional volumetrics, the SVM achieved the highest differentiation performance, with AUROCs of 0.937 (internal) and 0.914 (external). A radiology resident achieved improved performance with the model. Our proposed two-step algorithm combining deep-learning-based brainstem segmentation and machine-learning classification enables automated differentiation of Parkinsonian syndromes using 3D T1-weighted brain MRI. 3. Stage 1.

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

We report 18F-AV1451 PET/MRI findings of a 56-year-old man with progressive supranuclear palsy (PSP). The images revealed multifocal 18F-AV1451 tracer uptake in both intracranial and extracranial regions, with increased retention in bilateral basal ganglia regions and scalp soft tissue. The findings may reflect systemic tau pathology and provide the clinical experience for the possible assessment of the disease severity.

Imaging protocols for progressive supranuclear palsy (PSP) are increasingly incorporating different PET modalities-including 18F-fluorodeoxyglucose (18F-FDG; cerebral glucose metabolism), 18F-FP-CIT (dopamine transporter [DAT] activity), and 18F-Florzolotau (tau pathology) PET-to improve diagnostic accuracy. In this cross-sectional study, we characterized tracer-specific imaging patterns and evaluated their interrelationships in patients with PSP to clarify the underlying pathophysiological mechanisms. Twenty-eight patients with clinically diagnosed PSP underwent 18F-FDG, 18F-FP-CIT, and 18F-Florzolotau PET imaging. Quantitative voxel-based and region-of-interest analyses were conducted. Standardized uptake value ratios (SUVRs) were calculated and compared with sex-matched controls (n=20 per PET modality). In patients with PSP compared with controls, 18F-FDG PET revealed significant glucose hypometabolism in frontal, parietal, cerebellar, and subcortical regions. 18F-FP-CIT PET demonstrated reduced DAT availability in the striatum and midbrain. Finally, 18F-Florzolotau PET showed elevated tau deposition in the thalamus, midbrain, pons, and precentral gyrus. An inverse correlation linked midbrain tau burden with local glucose metabolism (r=-0.39, P=0.04). Frontal hypometabolism correlated strongly with subcortical metabolic deficits (r=0.61, P<0.001). Only the left putamen showed a moderate negative association between DAT loss and tau accumulation (r=-0.42, P=0.03). Patients with PSP exhibit metabolic deficits in cortical-subcortical networks, dopaminergic denervation in striatal-midbrain regions, and tau pathology localized to brainstem and thalamic areas. Tracer-specific SUVRs correlations revealed specific interplay among glucose hypometabolism, DAT deficiency, and tau accumulation.

Assess the palliative care needs of patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), focusing on symptom burden, quality of life, caregiver strain and future planning. A cross-sectional survey incorporating Integrated Palliative Outcome Scale-Neuro 24 (symptom assessment), Short Form 36 Health Survey (quality of life), an advance care planning survey and a validated caregiver quality of life questionnaire. 19 participants with a diagnosis of PSP or CBS, and 17 caregivers were included in the study, recruited from the Leinster Tauopathy Epidemiological Study.Most participants were male (74%) with a mean age of 72 and moderate to advanced disease (Hoehn and Yahr score: 3.6). Over half reported fatigue, urinary issues, pain, swallowing and communication difficulties, with falls and mobility problems being particularly common. Quality of life was significantly impaired, particularly in physical functioning and general health.Over 75% wanted earlier and practical information about their condition, more than 25% were hesitant to engage in conversations about prognosis and EOL care.Caregivers experienced high levels of burden, fatigue (89%), physical stress (82%), low mood (76%), neglect of personal health (54%) and loneliness (53%), highlighting the considerable physical and emotional challenges encountered. Understanding the complex symptoms and needs of this vulnerable population is key to effectively allocating resources, shaping integrated neurology and palliative care services, and ultimately improving quality of life for those living with these conditions.

Atypical parkinsonian syndromes, such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), are neurodegenerative disorders characterized by rapid progression, limited treatment options, and clinical overlap, as well as frequent misdiagnosis with Parkinson's disease (PD). Early and accurate diagnosis, together with reliable tools for prognosis, remain major unmet needs in their clinical management and for the design and interpretation of therapeutic clinical trials, particularly those aimed at disease-modification. Neurofilament light chain (NfL), a structural protein of the neuronal cytoskeleton released into cerebrospinal fluid (CSF) and blood after axonal injury, has emerged as a valuable biomarker in this context. Markedly elevated NfL levels are consistently found in MSA and PSP compared to PD, correlating with disease severity, brain atrophy, and survival. Although NfL has strong diagnostic and prognostic value at the group level, it marginally discriminates MSA from PSP as we show in this literature review and new analysis of our Barcelona cohort. Furthermore, NfL is influenced by age, comorbidities, and analytical variability. The correlation between its levels in CSF and blood, while consistently replicated, remains moderate, and their associations with clinical outcomes and disease progression are yet to be fully defined. This review summarizes current evidence on the role of NfL in MSA and PSP, covering its applications in diagnosis, prognosis, clinical trials, and real-world practice, as well as outlining the main challenges and future directions for its broader clinical translation.

Anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is a rare autoimmune encephalitis that shares clinical features with progressive supranuclear palsy (PSP), complicating differential diagnosis. Here, we sought to investigate whether PET imaging using [18F]Florzolotau and [18F]FDG could distinguish these disorders through characteristic patterns of tau deposition and cerebral glucose metabolism. Eleven patients with serologically confirmed anti-IgLON5 disease, 20 patients with PSP diagnosed according to the 2017 Movement Disorder Society criteria, and 40 age-matched and sex-matched healthy controls were enrolled. Participants underwent [18F]Florzolotau and/or [18F]FDG PET imaging. Visual interpretation and semiquantitative analyses, including voxel-based and region-of-interest approaches, were performed. Anti-IgLON5 patients showed significant [18F]Florzolotau binding in subcortical regions, including the midbrain, pons, caudate, putamen, and thalamus, along with additional involvement of the parietal lobe and cerebellum. PSP patients demonstrated overlapping [18F]Florzolotau uptake in the caudate, putamen, thalamus, midbrain, and pons, but with distinct additional binding in the frontal lobe. [18F]FDG PET revealed contrasting metabolic profiles: anti-IgLON5 disease was associated with diffuse cortical hypometabolism, whereas PSP showed regionally restricted hypometabolism, mainly in the frontal lobe, caudate, putamen, midbrain, and pons. We identified distinct PET signatures that can reliably differentiate anti-IgLON5 disease from PSP. The complementary application of [18F]Florzolotau and [18F]FDG PET imaging may provide valuable biomarkers for differential diagnosis in clinically ambiguous cases, potentially enabling timely immunotherapeutic interventions for patients with imaging patterns suggestive of anti-IgLON5 disease.

BackgroundAgitation is a clinically significant symptom contributing to behavioral and psychological symptoms of dementia (BPSD) but is poorly understood across the different syndromes related to Frontotemporal Lobar Degeneration (FTLD). This study investigates sex differences in agitation across FTLD‐related syndromes and its relationship to various neuropsychiatric symptoms (NPS).MethodWe analyzed data from 1,654 participants (916 males, 738 females; average ages 65.8 and 65.9, respectively) from the National Alzheimer's Coordinating Center (NACC) and ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study with a FTLD‐related syndrome: behavioral variant FTD (bvFTD), Primary Progressive Aphasia (non‐fluent variant (nfvPPA), semantic variant (svPPA)), Corticobasal syndrome (CBS) and Progressive Supranuclear Palsy (PSP). Participants’ symptoms were assessed using the Neuropsychiatric Inventory (NPI). Prevalence ratios and odds ratios were computed to assess the likelihood of NPS comorbidities when agitation was present in males and females. Principal Component Analysis (PCA) was performed to identify NPS associated with agitation and how they varied by sex.ResultMales were more likely to experience anxiety (bvFTD: p <0.001, CBS: p <0.01, PSP: p <0.0001), apathy (nfvPPA: p <0.01, PSP: p <0.01), depression (bvFTD: p <0.0001, PSP<0.01), disinhibition (nfvPPA: p <0.0001), PSP: p <0.001), and motor symptoms (bvFTD: p <0.01, CBS: p <0.01) when agitation was present. In contrast, females had a higher likelihood of experiencing disinhibition in svPPA (p <0.001). These findings suggest that agitation is associated with a wider range of NPS in males than in females. Agitation and NPS are especially prominent in males with PSP.ConclusionThis study reveals significant sex differences in NPS in FTLD‐related syndromes when agitation is present. Males and especially PSP, are more likely to experience a broader range of NPS in association with agitation. These findings underscore the need for further investigation into the underlying mechanisms driving these sex differences, particularly focusing on the neurobiological impact of agitation, the recognition of symptoms in the presence of greater behavioral disturbances, and potential variations from informant reports. Understanding these factors will provide valuable insights into the role of agitation in the presentation of NPS across FTLD‐related syndromes. Ultimately, addressing these gaps will enhance our ability to effectively treat and manage agitation in both male and female patients with FTLD‐related syndromes.

Progressive Supranuclear Palsy (PSP) shares cognitive and behavioral changes with Parkinson's Disease (PD) that challenge their differential diagnosis, especially in early stages. Changes in inhibitory control associated with impulse control disorders are often seen in PD, and related to dopaminergic treatment. We aimed to uncover distinct neuropsychological profiles particularly in the amount and type of errors within a standard cognitive assessment protocol. Participants included 29 patients with diagnosis of clinically probable PSP and 41 early-PD patients matched by disease duration. Assessment consisted of a standard 90-minute battery of neuropsychology widely-validated tests. We analyzed the presence of repetitions and perseverative errors across several tests: phonological and semantic fluency, Trail-making tests A/B, verbal memory lists (immediate and delayed recall), Go/No-Go, and Wisconsin-card sorting test. Results were co-variated by an attentional score. PSP patients exhibited significantly poorer performance than PD in verbal fluency, attention, and processing speed (TMT-A/B). In addition, PSP showed higher frequencies of perseverative and commission errors highlighting a specific profile with decreased flexibility and impaired inhibitory control in PSP compared to early-PD. PD patients did not use higher doses of dopaminergic treatment than PSP. The findings underscore the diagnostic value of specific error patterns in routine tasks used for assessing cognitive profiles in neurology. These profiles could serve as a bed-side tool to help in the early differentiation of PSP and PD, and show valuable insights into the pathophysiological mechanisms of inhibitory control in both diseases.