Citations

Abstract Background Progressive supranuclear palsy (PSP) is a tauopathy for which there is limited understanding of epidemiological risk factors. Objective The objective of this study was to identify premorbid nonmedical and medical risk factors for PSP diagnosis in a large prospective population‐based cohort. Methods We performed a matched nested case–control study using the UK Biobank (UKB) cohort consisting of >500,000 adults aged 37 to 73 years. PSP diagnoses were identified from 2007 to censor date (August 2025) and matched 1:10 by age and sex to control subjects without parkinsonism or dementia diagnoses. We derived risk factors using an iterative logistic regression approach. Results There were 240 incident PSP diagnoses in the UKB. In the fully adjusted model, premorbid depression (odds ratio [OR], 3.22; 95% confidence interval [CI], 2.30–4.50; P < 0.001), delirium (OR, 6.76; 95% CI, 4.08–11.19; P < 0.001), and functional gastrointestinal disorders (OR, 1.91; 95% CI, 1.39–2.63; P < 0.001) were associated with increased risk. Heavy alcohol consumption was associated with higher risk compared with moderate consumption (OR, 1.65; 95% CI: 1.21–2.26; P = 0.0017). Body mass index (BMI) and alcohol consumption had nonlinear risk profiles. Cancer diagnosis was inversely associated with PSP (OR, 0.56; 95% CI, 0.40–0.79; P < 0.001). Depression and delirium diagnoses remained significant 5 to 10 years before diagnosis. Conclusions In this large prospective cohort, PSP was associated with premorbid lifestyle practices and neuropsychiatric diagnoses years before diagnosis. This suggests a long premotor phase and highlights opportunities for earlier diagnosis and further mechanistic investigation. The inverse association with cancer mirrors the relationship seen in other neurodegenerative conditions and may point toward shared mechanisms. © 2026 International Parkinson and Movement Disorder Society.

Background Motor speech disorders are early, common, and functionally limiting features of atypical parkinsonian disorders (APDs) such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA). These impairments are underrecognized and undertreated in neurology clinics. Objectives This review aims to characterize speech impairment in APDs, offer practical guidance for clinical evaluation, highlight the role of Speech‐Language pathologists (SLPs) in diagnosis and management, and outline current and emerging management strategies. Methods A narrative review was conducted by the Diagnosis and Treatment Working Group of CurePSP's Centers of Care, integrating literature and clinical experience to summarize evaluation, diagnosis, and treatment of motor speech disorders in APDs. Results Speech changes in APDs are often mixed dysarthrias with hypokinetic, spastic, and/or ataxic components, and may include apraxia of speech; these are frequently more severe and progress quicker than in Parkinson's disease. These features can assist in differential diagnosis and should prompt early referral to SLPs. Despite the high prevalence of speech and voice changes, comprehensive assessment of motor speech disorders is uncommon in neurology clinics. Current evidence regarding the efficacy of interventions is mixed. Digital acoustic analysis and neuromodulation offer promising directions for diagnosis and treatment. Conclusions Early, collaborative management of motor speech impairment elevates care in APDs. Neurologists and SLPs must work together to improve recognition, diagnosis, and care. Future research should focus on objective biomarkers and personalized therapies to support communication, autonomy, and quality of life for individuals living with APDs.

Abstract Background Progressive Supranuclear Palsy (PSP) is a rare and severe neurodegenerative tauopathy characterized by diverse clinical phenotypes, including Richardson's syndrome (PSP‐RS), PSP‐parkinsonism (PSP‐P), PSP‐progressive gait freezing (PSP‐PGF), and PSP‐corticobasal syndrome (PSP‐CBS). Significant geographic variation exists in prevalence, clinical presentations, and prognosis. Objectives This global review aims to systematically evaluate the epidemiological variation, clinical phenotypes, diagnostic practices, and management strategies for PSP, focusing on regional disparities and identifying influencing genetic and environmental factors. Methodology A comprehensive literature search following PRISMA guidelines was conducted, analyzing studies reporting PSP epidemiology, phenotypes, diagnostic criteria, risk factors, treatments, and prognoses. Data were categorized into epidemiology, risk factors, clinical presentations, diagnosis, treatment accessibility, and outcomes, considering geographic variation. Results Global PSP prevalence ranges between 5–6.4 per 100,000, influenced by diagnostic criteria and healthcare infrastructure. Clinical manifestations commonly include supranuclear gaze palsy, frequent falls, cognitive impairment, and motor dysfunction. Prognosis significantly varies with subtype; PSP‐RS shows rapid progression and shorter survival (5–7 years), whereas PSP‐P has a milder clinical course (8–12 years). Regional variations highlight differences in genetic predispositions, notably the MAPT H1 haplotype, environmental risk factors such as dietary neurotoxins and industrial pollutants, and accessibility to comprehensive healthcare services. Diagnostic accuracy has improved with the adoption of MDS‐PSP criteria, facilitating recognition of diverse phenotypes. Conclusions Regional disparities in PSP prevalence, phenotypic presentation, and healthcare accessibility underscore the importance of standardized diagnostic criteria, targeted genetic and environmental studies, and equitable healthcare strategies. Enhanced global collaboration is essential for improving PSP diagnosis, management, and patient outcomes worldwide.

AbstractBackgroundThere is a critical need for tau PET radiotracers that accurately detect non‐Alzheimer’s disease (AD) tau pathology. We aim to evaluate [18F]PI‐2620 PET tracer retention in patients with non‐AD, 4R tau‐related clinical syndromes, including progressive supranuclear palsy (PSP) with Richardson’s syndrome (PSP‐RS) and with predominant parkinsonism (PSP‐P), corticobasal syndrome (CBS), and nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA).Method38 participants underwent amyloid and [18F]PI‐2620 PET (Table 1). 5 mCi ± 10% of [18F]PI‐2620 was administered. [18F]PI‐2620 PET SUVR images were generated using an inferior cerebellar gray matter reference from PET data acquired 30‐60 minutes post‐injection. Mean SUVR values were extracted from each participant in neuroanatomical structures that have elevated tau burden in PSP and CBS due to corticobasal degeneration (regions of interest in Table 2). Comparison between each diagnostic group and healthy controls (HCs) was performed using a one‐tailed, independent‐samples t‐test. Spearman correlation was used to evaluate the relationship between tracer binding (SUVR) and disease severity (PSP rating scale) in patients with PSP‐RS.ResultPatients with PSP‐RS had increased tracer retention in the left globus pallidus internus and externus, left subthalamic nucleus, and left dorsolateral prefrontal cortex compared to HCs (all p < 0.05). CBS and nfvPPA patients did not have increased tracer retention at any ROIs compared to HCs, but there were low numbers of patients in these groups (Table 2, Figures 1‐3). PSP rating scale values did not correlate with tracer binding in PSP‐RS (no correlations in any regions, rs < 0.44, p > 0.05 uncorrected).Conclusion[18F]PI‐2620 PET 30‐60 minute SUVR images may have limited ability to distinguish PSP from HCs, especially on visual read, and tracer uptake did not correlate with PSP disease severity. Other post‐injection PET acquisition windows (e.g., 30‐40 minute SUVR, 0‐60 minute DVR) will be evaluated to determine if they can maximize differences between PSP and HCs. A limitation of this preliminary study is the modest number of patients and controls, with most controls provided from a different study. Additional participants are being scanned in the multicenter 4RTNI study to understand the utility of this tracer as a neuroimaging biomarker for 4R tauopathies.

ABSTRACT Background Multiple System Atrophy is a rare neurodegenerative disease with alpha‐synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome‐wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy‐confirmed cases. Methods We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results The most strongly disease‐associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P ‐values below 5 × 10 −6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4‐immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4‐mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates.ObjectiveThe objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD.MethodsAdvancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation.Results29% of respondents self‐reported as patients (63±10 years), 26% self‐reported as caregivers answering on behalf of patients (65±10 years), and 45% self‐reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%).ConclusionsFavorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation.

AbstractBackground and purposeSeveral clinical and demographic factors relate to anatomic spread of adult‐onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult‐onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread.MethodsAdult‐onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation (“dystonia‐only”) and one accepting dystonia OR tremor in any body part as disease manifestations (“dystonia OR tremor”). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping.ResultsBoth predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62–0.70 and 0.62–0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread.ConclusionsThis predictive modeling of spread in adult‐onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals’ risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.

AbstractBackgroundIt is important to determine the natural history of sporadic and familial frontotemporal lobar degeneration (FTLD) and generate clinical, neuropsychological, neuroimaging and biofluid data for planning disease‐modifying trials.MethodAs part of the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD; U19 AG063911) protocol, investigators at 19 centers in North America will enroll 2100 participants with FTLD over the next 5 years beginning in early 2020.ResultAs of 1/20/20, the ARTFL/LEFFTDS (A/L) Consortium had enrolled 1832 participants, including 850 in kindreds with familial FTLD (239 associated with mutations in MAPT, 192 in GRN, 370 in C9orf72, 4 with mutations in both GRN and C9orf72, and 45 with a mutation in a different gene or no mutation in any known FTLD‐associated gene). Over 500 participants have undergone 2 or more annual visits to date. MRI has been performed in 1105. Biofluid samples have also been collected, with blood (DNA, plasma, serum, mRNA, PBMC) in 1413 and CSF in 303. Over 60 manuscripts using A/L data or samples have been published to date. Five clinical trials involving A/L and ALLFTD participants are in progress or planned. The longitudinal arm in ALLFTD will enroll 500 of existing A/L and 600 future participants for annual assessments with similar methodology to A/L. An additional 1000 FTLD patients will undergo focused one‐time clinical evaluations and biofluid collection.ConclusionThe data/samples from already‐enrolled and planned participants in ALLFTD and findings published to date underscore the utility of evaluating FTLD subjects. The absence of identifiable mutations in some with familial FTLD suggests that other genes are yet to be discovered. ALLFTD data will inform clinical trial design, and many participants will be eligible for future trials. The key data and samples in ALLFTD are available to interested investigators worldwide. Supported by: AG063911, AG045390, NS092089, AG016976, AG21886.