Environmental Risk Factors for Progressive Supranuclear Palsy

Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied. To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD. This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019. Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures. A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05). These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.

Considerable evidence suggests that midbrain-based magnetic resonance Parkinsonism index (MRPI) measurements are reliable biomarkers for the diagnosis of progressive supranuclear palsy (PSP). However, the longitudinal atrophy pattern of PSP and potential differences in change rates among PSP phenotypic spectrum remain unclear. This study aims to investigate the longitudinal changes of MRPI measurements and explore their potential role in PSP phenotype progression monitoring. Thirty-six patients with PSP-Richardson's syndrome (PSP-RS), 21 patients with variant PSP (vPSP), and 21 healthy controls (HCs) with longitudinal MRI and clinical follow-up were enrolled. Midbrain-based morphometric measurements and the corresponding annual percentage changes (APCs) were measured and further used to evaluate the associations with disease progression. Significant differences in midbrain-based morphometric biomarkers were observed both at baseline and longitudinal trajectories between PSP and HC groups, but no significant differences were found between PSP-RS and vPSP subgroups. Baseline comprehensive measurements were significantly associated with the baseline PSP rating scale (PSPrs) in all PSP and PSP phenotypes. The APC of MRPI was significantly associated with the APC of PSPrs in all PSP (r = 0.267, p = 0.046) and the PSP-RS subgroup (r = 0.386, p = 0.020). This study characterizes the longitudinal atrophy trajectory of PSP phenotypes and the significant associations between morphometric measurements and disease severity. Dissecting the causal associations among core 4R-tau, dopamine, and subsequent atrophy trajectories may enhance the application of these biomarkers for phenotype attribution. Questions The use of midbrain-based MRPI measurements to assess the longitudinal prognosis of the PSP phenotype remains uncertain. Findings Significant differences in midbrain-based morphometric biomarkers were observed both at baseline and longitudinal trajectories between PSP and health control groups. Clinical relevance Midbrain-based morphometric measurements hold promise as potential radiological biomarkers for monitoring PSP disease progression and assessment.

Progression of two Progressive Supranuclear Palsy phenotypes with comparable initial disability

Although diagnostic criteria and research are constantly advancing, distinguishing between progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) remains a significant challenge. This difficulty stems from their similar clinical symptoms and the lack of reliable biomarkers. In this work, we present a detailed review of fluorodeoxyglucose (FDG)–positron emission tomography (PET), exploring its potential role in differentiating PSP and CBS, drawing on their established utility in other neurodegenerative diseases. We searched the PubMed database from its inception for original research articles assessing the utility of FDG-PET for the diagnosis or differential diagnosis of PSP and CBS from other neurodegenerative conditions. A total of 91 studies were eligible. These 91 studies were categorized as follows: (a) 20 studies included only patients with PSP, (b) 15 studies included only patients with CBS, (c) 39 studies involved patients with Parkinson’s disease and atypical Parkinsonian disorders, including subgroups of PSP and/or CBS, and (d) 17 studies compared patients with PSP and/or CBS to individuals with Alzheimer’s disease, frontotemporal dementia, or other dementias. Most FDG-PET studies involving PSP and CBS were not specifically designed for these disorders. An additional obstacle lies in the methodological variability across studies. Despite several studies achieving high diagnostic accuracy for PSP and/or CBS with specificity exceeding 90% using FDG-PET, sensitivity remains considerably lower. CBS appears to have a distinct hypometabolic pattern compared to PSP, marked by asymmetry and predominant cortical involvement. CBS more often affects posterior cortical regions (parietal and posterior parts of the frontal cortex, and sometimes temporal and occipital parts) and the thalamus, whereas PSP appears to affect the striatum, frontal cortex, anterior cingulate, and subtentorial structures, typically in a more symmetrical manner. Large, multicenter studies are needed, utilizing standardized imaging and protocols.

Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study

There is no disease-modifying treatment of corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), 2 disorders characterized by their striking phenotypic, and, in CBS, pathologic heterogeneity. Seed amplification assays (SAAs) could enable the detection of neuropathologic processes, such as α-synuclein (αSyn) copathology, that affect the success of future disease-modifying treatment strategies. The primary objective was to assess possible αSyn copathology in CBS and PSP, as detected in CSF using an αSyn SAA (αSyn-SAA). Secondary objectives were to evaluate the association of αSyn-SAA positivity with other biomarkers including of Alzheimer disease (AD), and with clinical presentation. We hypothesized that αSyn-SAA positivity would be detectable in CBS and PSP and that it would be associated with AD biomarker positivity and β-amyloid (Aβ) 42 levels, neurodegeneration as assessed by neurofilament light chain (NfL) levels, and symptoms associated with synucleinopathies. This cross-sectional observational study included patients clinically diagnosed with CBS and PSP who underwent a lumbar puncture between 2012 and 2021 (Toronto Western Hospital, Canada). CSF was tested for αSyn-SAA positivity, AD biomarkers, and NfL levels. Clinical data were derived from medical records. We tested the CSF of 40 patients with CBS (19 female patients, 65.9 ± 8.6 years) and 28 with PSP (13 female patients, 72.5 ± 8.7 years old), mostly White (n = 50) or Asian (n = 14). αSyn-SAA positivity was observed in 35.9% patients with CBS and 28.6% with PSP. In young-onset, but not late-onset patients, αSyn-SAA positivity and AD positivity were associated (odds ratio [OR] 8.8, 95% CI 1.2-82.6, p < 0.05). A multivariable linear regression analysis showed a significant interaction of αSyn-SAA status by age at onset on CSF Aβ42 levels (β = 0.3 ± 0.1, p < 0.05). Indeed, age at onset was positively related to Aβ42 levels only in αSyn-SAA-positive patients, as shown by slope comparison. A logistic regression analysis also suggested that REM sleep behavior disorder was associated with αSyn-SAA positivity (OR 60.2, 95% CI 5.2-1,965.8; p < 0.01). We detected a frequency of αSyn-SAA positivity in CBS and PSP in line with pathologic studies, highlighting the usefulness of SAAs for in vivo detection of otherwise undetectable neuropathologic processes. Our results also suggest that AD status (specifically low Aβ42) and older age at onset may contribute to αSyn-SAA positivity. This opens new perspectives for the stratification of patients in clinical trials.

Progressive supranuclear palsy (PSP) is typically manifested by vertical supranuclear gaze palsy, frequent falls early in the disease course, axial rigidity and poor response to levodopa. Prominent anterograde memory dysfunction with subsequent impairment in other cognitive domains is characteristic of Alzheimer’s disease (AD). No clear clinical syndrome has been identified in argyrophilic grain disease (AGD). Frontotemporal dementia (FTD) is characterized by apathy, emotional blunting, disinhibition, and impairment in executive functioning despite relatively preserved memory and visuospatial abilities. Cognitive deficits are known to occur in PSP; however, overt clinical FTD without parkinsonism or supranuclear gaze palsy associated with PSP pathology has rarely been documented. We report an elderly patient with the typical clinical, neuropsychometric, and neuroimaging features of FTD who had autopsy findings most consistent with PSP plus AGD and AD in limbic structures. We suggest that PSP with or without coexisting AD and AGD be included in the differential diagnosis of patients presenting with FTD.

Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), although it is unclear whether it is associated with the PSP syndrome (PSPS) or PSP pathology. The aim of the present study was to determine whether midbrain atrophy is a useful biomarker of PSP pathology, or whether it is only associated with typical PSPS. All autopsy-confirmed subjects were identified with the PSP clinical phenotype (i.e. PSPS) or PSP pathology and a volumetric MRI. Of 24 subjects with PSP pathology, 11 had a clinical diagnosis of PSPS (PSP-PSPS), and 13 had a non-PSPS clinical diagnosis (PSP-other). Three subjects had PSPS and corticobasal degeneration pathology (CBD-PSPS). Healthy control and disease control groups (i.e. a group without PSPS or PSP pathology) and a group with CBD pathology and corticobasal syndrome (CBD-CBS) were selected. The midbrain area was measured in all subjects. [Correction added on 21 June 2013, after first online publication: the abbreviation of corticobasal degeneration pathology was changed from CBD-PSP to CBD-PSPS.] The midbrain area was reduced in each group with clinical PSPS (with and without PSP pathology). The group with PSP pathology and non-PSPS clinical syndromes did not show reduced midbrain area. Midbrain area was smaller in the subjects with PSPS than in those without PSPS (P<0.0001), with an area under the receiver operator curve of 0.99 (0.88, 0.99). A midbrain area cut-point of 92mm(2) provided optimum sensitivity (93%) and specificity (89%) for differentiation. Midbrain atrophy is associated with the clinical presentation of PSPS, but not with the pathological diagnosis of PSP in the absence of clinical PSPS. This finding has important implications for the utility of midbrain measurements as diagnostic biomarkers for PSP pathology.

IntroductionFrontotemporal lobar degeneration (FTLD) includes heterogenous diseases: behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasias (PPA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We applied neuroanatomical normative modelling to quantify individual atrophy patterns and heterogeneity within and between FTLD forms.MethodsWe included 160 participants across FTLDNI and 4RTNI studies: controls (n = 15), bvFTD (n = 22), nfvPPA (n = 14), svPPA (n = 21), CBS (n = 43) and PSP (n = 45). Using cortical thickness and subcortical volumes from 3T MRIs, we applied normative modelling with a large healthy reference dataset (n = 58,836), further accounting for age, sex, and scanner. Outlier regions (z < – 1.96) were used to compute total outlier counts (tOC) and Hamming distances, capturing individual atrophy patterns and inter-subject dissimilarity.ResultsbvFTD, svPPA, CBS and PSP showed significantly higher cortical tOC than controls, with all groups showing higher subcortical tOC than controls, especially svPPA and PSP. bvFTD, svPPA, CBS and PSP had significantly higher cortical Hamming distance scores than controls, with higher scores in bvFTD and svPPA than nfvPPA and PSP. svPPA and PSP had significantly higher subcortical scores than controls and CBS. Greater disease severity (measured using the Clinical Dementia Rating—CDR for PSP and CBS, and the CDR® plus NACC-FTLD global scores for FTD variants) was associated with increased tOC and dissimilarity, highlighting the link between clinical progression and neuroanatomical heterogeneity.ConclusionsThe pronounced heterogeneity within and between FTLD subtypes (particularly in bvFTD) increases with disease progression and may reflect distinct underlying pathologies. This supports the development of subtype-specific biomarkers and emphasize the need for personalized diagnostic and therapeutic strategies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-025-13378-5.

Phenotypic heterogeneity of progressive supranuclear palsy (PSP) has been increasingly reported in the literature and can be the source of incorrect clinical diagnosis particularly in the early stages of the disease when the classically associated symptoms of early falls and supranuclear gaze palsy may not be apparent. In addition to Richardson syndrome (RS), several atypical clinical phenotypes have been described. Advances in genetic, neuroimaging, and biochemical/molecular technologies contribute to the identification of these clinical subtypes in the context of typical PSP pathological findings. Our goal is to review the phenomenology reported in the literature that is associated with confirmed histopathological changes consistent with a PSP diagnosis and to highlight the clinical spectrum of PSP. A systematic review of the literature in PubMed through July 2015 using MeSH terms and key words related to PSP was conducted. Articles describing PSP classifications, diagnostic criteria, and case reports were reviewed and summarized. Additional PSP phenotypes not seen in recent clinicopathological studies are included. These include primary lateral sclerosis, pallido-nigro-luysian degeneration, axonal dystrophy, and multiple system atrophy in the spectrum of atypical PSP variants beyond the traditionally classified PSP subtypes. This review is intended to help with the diagnostic challenges of atypical PSP variants. We believe that large multicenter clinicopathological studies will help expand our understanding of etiology and specific mechanisms of neurodegeneration and will aid in the appropriate interpretation of outcomes when conducting clinical and basic science research.

To examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents. Six- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial. Patients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale. Volume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects.

The language profile of progressive supranuclear palsy

Objective Clinicopathological studies over the last decade have broadened the clinical spectrum of progressive supranuclear palsy (PSP) to include several distinct clinical syndromes. We examined the cognitive profiles of patients with PSP-Richardson’s syndrome (PSP-RS) and two atypical ‘brainstem predominant’ PSP phenotypes (PSP-parkinsonism, PSP-P; and PSP-pure akinesia with gait freezing, PSP-PAGF) using a comprehensive neuropsychological battery.Methods Fourteen patients diagnosed as PSP-RS, three patients with PSP-P and four patients with PSP-PAGF were assessed using a comprehensive battery of neuropsychological tests.Results The typical PSP-RS subgroup demonstrated greater impairments in processing speed [t(19) = -4.10, p = 0.001 (d =1.66)] and executive function [t(19) = -2.63, p = 0.02 (d = 1.20)] compared to the ‘brainstem predominant’ PSP phenotype.Conclusion This is the first prospective study to demonstrate that PSP-RS and ‘brainstem predominant’ PSP phenotypes can be differentiated on cognitive grounds. These differences correspond with variations in pathological profiles reported in the literature.

Synaptic loss is prominent in several human neurodegenerative diseases. We tested the hypothesis that synaptic density is reduced by the primary tauopathies of progressive supranuclear palsy (PSP) and cor- ticobasal syndrome (CBS). Thirty-three participants (10 CBS, 10 PSP, and thirteen age-/sex-/education- matched controls) underwent clinical and neuropsychological assessment, 3T-magnetic resonance imaging, and positron emission tomography with the radioligand [11C]UCB-J which targets the Synaptic Vesicle Glycoprotein 2A (SV2A). Eight CBS patients had negative β-amyloid biomarker. As expected, PSP and CBS groups were impaired in executive, memory and visuospatial tasks. [11C]UCB-J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala and subcortical structures in both PSP and CBS patients compared to controls (p&lt;0.001), with reductions up to 50%, consistent with post mortem data. The revised Addenbrooke’s Cognitive Examination score correlated positively with cortical [11C]UCB-J binding (frontal, temporal, parietal, and occipital lobes, hippocampus, insula and amygdala, all p&lt;0.05); putamen and precentral [11C]UCB-J binding correlated inversely with the PSP rating scale (both p&lt;0.05). In conclusion, we confirm severe synaptic loss in PSP and CBS, which correlates with disease severity, providing critical insights into the underlying pathophysiology of primary degenerative tauopathies and supporting potential treatment strategies based on synaptic maintenance or restoration.nda26@cam.ac.uk

records were collected on an annual basis and all pertinent information was entered into a database. For patients with cognitive impairment a caregiver with knowledge of the patient’s family and personal medical history completed the registry form. Upon death, remaining medical records were collected and neuropathological analyses were performed. Patients were brought to autopsy according to standardized protocols for brain handling and processing. The clinical diagnosis of PSP was made either by movement disorders specialists and/or general neurologists before death and was clearly documented in the medical fi les. Two patients were only evaluated by a general neurologist. Multiple documented neurological evaluations throughout the course of the patients’ illness were reviewed. Diagnoses were re-confi rmed after death by a movement disorders specialist (S.P.), who applied standard criteria for PSP [4] (vertical supranuclear gaze palsy, prominent postural instability, falls in the fi rst year of onset, and no evidence of other disorders to explain the neurologic fi ndings). Diagnoses of dementia and psychiatric disorders were made by the patients’ treating physicians and were clearly documented in the medical fi les. Clear documentation of dementia included diagnosis by a psychiatrist, formal psychometric testing and/or Mini-Mental State Examination ! 24 [5] . The characterDear Sir, Progressive supranuclear palsy (PSP) is the most common and best recognized atypical parkinsonian syndrome. The clinical characteristics of PSP as described by Steele, Richardson and Olszewsky [1] in 1964 include parkinsonian features, postural instability, vertical supranuclear gaze palsy, pseudobulbar symptoms and cognitive decline. However, it has been widely recognized that PSP is characterized by an ever-expanding and ‘diverse’ clinical phenotype [2] that among others includes a fl orid neuropsychiatric symptomatology [3] . This report focuses on the description of hallucinations in a small cohort of clinically and pathologically diagnosed PSP patients. Our study population consisted of 22 consecutive PSP patients. All subjects consented during life to donate their brains to the University of Miami Brain Endowment Bank TM . Brain donors were recruited and registered with the Brain Bank through a campaign performed throughout the United States over the last decade. All donors completed the Brain Bank’s PD registry form (a 128-item, self-administered questionnaire) providing information about demographics, environmental exposures, personal and family history, activities of daily living, clinical and treatment details. Yearly updates on all brain donors were obtained until death. Medical and hospital Received: July 7, 2005 Accepted: September 28, 2005 Published online: January 6, 2006