Progressive Supranuclear Palsy Subtypes Research Articles

Cerebral tau deposition in co-morbid progressive supranuclear palsy and amyotrophic lateral sclerosis: an [18F]-flortaucipir and 7T MRI study.

Introduction Progressive supranuclear palsy (PSP) is a four-repeat tauopathy characterized by multiple clinicopathologic subtypes. Advanced neuroimaging techniques have shown an early ability to distinguish PSP subtypes non-invasively for improved diagnosis. This study utilized tau-PET imaging and MRI techniques at 7 Tesla (7T) to determine the neuroimaging profile of a participant with comorbid PSP and amyotrophic lateral sclerosis (ALS). Method [18F]-flortaucipir PET imaging was performed on one participant with PSP-ALS, one participant with typical PSP (Richardson's syndrome; PSP-RS), and 15 healthy control volunteers. Standardized uptake value ratio (SUVR) in each brain region was compared between PSP participants and controls. Quantitative susceptibility mapping (QSM) and inflow-based vascular-space occupancy (iVASO) MRI at 7T were performed on the two PSP participants and on two age-matched healthy controls to evaluate for differences in regional brain iron content and arteriolar cerebral blood volume (CBVa), respectively. Results In the participant with PSP-ALS, the precentral gyrus demonstrated the highest [18F]-flortaucipir uptake of all brain regions relative to controls (z-score 1.94). In the participant with PSP-RS, [18F]-flortaucipir uptake relative to controls was highest in subcortical regions, including the pallidum, thalamus, hippocampus, and brainstem (z-scores 1.08, 1.41, 1.49, 1.32, respectively). Susceptibility values as a measure of brain iron content were higher in the globus pallidus and substantia nigra than in the midbrain and pons in each participant, regardless of group. CBVa values tended to be higher in the subcortical gray matter in PSP participants than in controls, although large measurement variability was noted in controls across multiple regions. Conclusion In vivo tau PET imaging of an individual with PSP-ALS overlap demonstrated increased tau burden in the motor cortex that was not observed in PSP-RS or control participants. Consistent with prior PET studies, tau burden in PSP-RS was mainly observed in subcortical regions, including the brainstem and basal ganglia. QSM data suggest that off-target binding to iron may account for some but not all of the increased [18F]-flortaucipir uptake in the basal ganglia in PSP-RS. These findings support existing evidence that tau PET imaging can distinguish among PSP subtypes by detecting distinct regional patterns of tau deposition in the brain. Larger studies are needed to determine whether CBVa is sensitive to changes in brain microvasculature in PSP.

Correlation between clinical and neuropathological subtypes of progressive supranuclear palsy

IntroductionProgressive supranuclear palsy (PSP) is characterized by pathology prominently in the basal ganglia, the tegmentum of the brainstem, and the frontal cortex. However, pathology varies according to clinical features. This study aimed to statistically verify the correspondence between the clinical and pathological subtypes of PSP. MethodsWe identified patients with a pathological diagnosis of PSP and classified the eight clinical subtypes of the Movement Disorders Society criteria for the clinical diagnosis of PSP (MDS-PSP criteria) into the Richardson, Akinesia, and Cognitive groups. We used anti-phosphorylated tau antibody immunostaining to semi-quantitatively evaluate neurofibrillary tangles (NFTs) and coiled bodies/threads (CB/Ths) in the globus pallidus, subthalamic nucleus, and midbrain tegmentum. In the frontal cortex, tufted astrocytes (TAs) and CB/Ths were assessed on a 3-point scale. We compared the pathology among the three groups, recorded the phenotypes ranked the second and lower in the multiple allocation extinction rule and examined whether the pathology changed depending on applying each phenotype. ResultsThe Richardson group exhibited severe NFTs and CB/Ths in the midbrain tegmentum. The Akinesia group showed severe NFTs in the globus pallidus. The Cognitive group had severe TAs and CB/Ths in the frontal cortex. TAs and CB/Ths in the frontal cortex correspond to behavioral variant frontotemporal dementia, and supranuclear vertical oculomotor palsy. ConclusionThese clinical symptoms may reflect the distribution of tau pathologies in PSP.

The significance of glial cell line-derived neurotrophic factor analysis in Progressive Supranuclear Palsy

Progressive Supranuclear Palsy (PSP) is an atypical parkinsonism. Major subtypes of the disease: PSP-Richardson’s Syndrome (PSP-RS) and PSP Parkinsonism Predominant (PSP-P) vary in clinical features, the pathomechanism remains unexplored. The aim of this work is to analyze the relevance of glial cell line-derived neurotrophic factor (GDNF) evaluation in the serum and cerebrospinal fluid (CSF) in PSP subtypes and to verify its significance as a possible factor in the in vivo examination. Authors assessed the concentration of GDNF in the serum and CSF of 12 patients with PSP-RS, 12 with PSP-P and 12 controls. Additionally authors evaluated patients using Unified Parkinson’s Disease Rating Scale—III part (UPDRS-III), Frontal Assessment Battery (FAB) and Magnetic Resonance Imaging (MRI). The evaluation revealed significantly increased concentrations of GDNF in the CSF among PSP-RS patients and substantially increased concentrations of GDNF in the serum in PSP-P. Though the GDNF concentrations differentiated PSP subtypes, no correlations between with clinical factors were observed however certain correlations with atrophic changes in MRI were detected. GDNF is a factor which may impact the pathogenesis of PSP. Possible implementation of GDNF as a therapeutic factor could be a perspective in the search for therapy in this currently incurable disease.

Uncovering distinct progression patterns of tau deposition in progressive supranuclear palsy using [18F]Florzolotau PET imaging and subtype/stage inference algorithm

Progressive supranuclear palsy (PSP) is a primary 4-repeat tauopathy with diverse clinical phenotypes. Previous post-mortem studies examined tau deposition sequences in PSP, but invivo scrutiny is lacking. We conducted [18F]Florzolotau tau positron emission tomography (PET) scans on 148 patients who were clinically diagnosed with PSP and 20 healthy controls. We employed the Subtype and Stage Inference (SuStaIn) algorithm to identify PSP subtype/stage and related tau patterns, comparing clinical features across subtypes and assessing PSP stage-clinical severity association. We also evaluated functional connectivity differences among subtypes through resting-state functional magnetic resonance imaging. We identified two distinct subtypes of PSP: Subtype1 and Subtype2. Subtype1 typically exhibits a sequential progression of the disease, starting from subcortical and gradually moving to cortical regions. Conversely, Subtype2 is characterized by an early, simultaneous onset in both regions. Interestingly, once the disease is initiated, Subtype1 tends to spread more rapidly within each region compared to Subtype2. Individuals categorized as Subtype2 are generally older and exhibit less severe dysfunctions in areas such as cognition, bulbar, limb motor, and general motor functions compared to those with Subtype1. Moreover, they have a more favorable prognosis in terms of limb motor function. We found significant correlations between several clinical variables and the identified PSP SuStaIn stages. Furthermore, Subtype2 displayed a remarkable reduction in functional connectivity compared to Subtype1. We present the evidence of distinct invivo spatiotemporal tau trajectories in PSP. Our findings can contribute to precision medicine advancements for PSP. This work was supported by grants from the National Natural Science Foundation of China (number 82272039, 81971641, 82021002, and 92249302); Swiss National Science Foundation (number 188350); the STI2030-Major Project of China (number 2022ZD0211600); the Clinical Research Plan of Shanghai Hospital Development Center of China (number SHDC2020CR1038B); and the National Key R&D Program of China (number 2022YFC2009902, 2022YFC2009900), the China Scholarship Council (number 202006100181); the Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198).

Progressive Supranuclear Palsy: A Review

Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease which is caused by 4 repeat tau proteins.  PSP has a low diagnosis rate because it is underdiagnosed or misdiagnosed as other common diseases such as Parkinson’s Disease (PD). A systematic and comprehensive literature review has been conducted with evidence from various sources in the databases of PubMed, Google Scholar, and JSTOR.  A synthesis was conducted based on “Progressive Supranuclear Palsy” in etiology and differential diagnosis was conducted based on “‘Parkinson’s disease’ on the way to progressive supranuclear palsy: a review on PSP-parkinsonism.”  From the results we can see that there is a lack of research overall for PSP and it is greatly understudied. One area that needs to be focused on is the treatment for disease-modifying symptoms of PSP as mostly only PD medications are used even though both the diseases are vastly different.  A systematic literature review has been done on the topic of PSP regarding the current advances. In general, the diagnosis of PSP is lacking as there is misdiagnosis between one of the PSP subtypes, PSP-Parkinsonism (PSP-P), and PD while there is also underdiagnosis as they symptoms of PSP-Richardson’s Syndrome is seen as natural aging. The lack of early diagnosis and validated biomarkers makes it difficult to find a treatment for PSP.  With the lack of information about PSP it is imperative that systematic research needs to be done so that patients have a favorable course and better standard of living.

Frequency of anti-IgLON5 disease in patients who meet the clinical diagnostic criteria for progressive supranuclear palsy/corticobasal syndrome (S22.010)

<h3>Objective:</h3> To confirm the prevalence of anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease in patients who fulfill the diagnostic criteria for progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS). <h3>Background:</h3> Anti-IgLON5 disease can present symptoms that mimic PSP and CBS, including vertical supranuclear gaze palsy and parkinsonism. Some patients who are diagnosed with PSP or CBS are expected to have anti-IgLON5 antibodies; however, the frequency of such patients remains unknown. <h3>Design/Methods:</h3> We included 360 subjects enrolled in the Japanese Longitudinal Biomarker Study in PSP and Corticobasal Degeneration (JALPAC). We noted the age and sex of each patient and evaluated their diagnosis using diagnostic criteria for each subtype of PSP (PSP with Richardson’s syndrome [PSP-RS], PSP with parkinsonism [PSP-P], PSP-pure akinesia with gait freezing [PSP-PAGF], and PSP with cerebellar ataxia [PSP-C]), and using the revised Cambridge criteria and Armstrong criteria for CBS. In patients who fulfilled any diagnostic criteria, we then tested serum anti-IgLON5 antibodies via a cell-based assay. <h3>Results:</h3> Of 360 subjects in JALPAC, 223 fulfilled at least one of the diagnostic criteria for possible or probable PSP/CBS. The median age of these 223 patients was 73 (range 51–88) years; 123 (55%) were male. The numbers of patients who met each set of criteria were as follows: PSP-RS, 52; PSP-PAGF, 6; PSP-C, 2; CBS, 117; PSP-RS and CBS, 37; PSP-PAGF and CBS, 4; PSP-RS and PSP-PAGF, 1; PSP-RS and PSP-P, 1; PSP-P and CBS, 1; PSP-RS, PSP-PAGF, and CBS, 1; and PSP-RS, PSP-C, and CBS, 1. All 223 patients were negative for anti-IgLON5 antibodies. <h3>Conclusions:</h3> Anti-IgLON5 disease is likely absent or extremely rare in patients who meet the diagnostic criteria for PSP/CBS and have typical clinical presentations. Atypical symptoms such as sleep disturbance, dysautonomia, and respiratory failure may be crucial clinical features of anti-IgLON5 disease with PSP-/CBS-like presentations. <b>Disclosure:</b> Yoya Ono has nothing to disclose. Akira Takekoshi has nothing to disclose. Dr. Yoshikura has nothing to disclose. Dr. Takigawa has nothing to disclose. Ikuko Aiba has nothing to disclose. Ritsuko Hanajima has nothing to disclose. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for DAIICHI SANKYO COMPANY, LIMITED. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eli Lilly Japan K.K.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Otsuka Pharmaceutical Co., Ltd.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen Inc.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda Pharmaceutical Company Limited.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Kyowa Kirin Co., Ltd.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Chugai Pharmaceutical Co., Ltd.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for ONO PHARMACEUTICAL CO., LTD.. Dr. Kanazawa has nothing to disclose. Dr. ?? has nothing to disclose. Aya Tokumaru has nothing to disclose. Dr. Morita has nothing to disclose. Dr. Hasegawa has nothing to disclose. Kenji Nakashima has nothing to disclose. Dr. Ikeuchi has nothing to disclose. Dr. Kimura has nothing to disclose. Dr. Shimohata has nothing to disclose.

Structural and Functional Thalamic Changes in Progressive Supranuclear Palsy

AimsStudies of thalamic structure and function in Progressive Supranuclear Palsy (PSP) suggest it may play a role in key aspects of the clinical syndrome. This study examined thalamic changes across PSP phenotypes investigating (i) thalamic atrophy (ii) thalamic functional connectivity and (iii) the relationship between thalamic structural and functional connectivity changes with clinical severity.MethodsParticipants92 participants with PSP [63 PSP-Richardson's Syndrome (RS), 24 PSP-cortical, 5 PSP-subcortical] and 104 age-matched controls were recruited from the Cambridge Centre for Parkinson's Plus Disorders cohort. Clinical assessments and imaging were conducted within 1 year of diagnosis.Structural AnalysisThalamic volumes (TVs) were obtained using FreeSurfer. Bayesian multiple regression (brms, R) was used to model (i) mean TVs (ii) group differences in mean TVs (iii) relationships between Z-standardised clinical scores and TVs with age, gender, and total grey matter as covariates.Functional AnalysisVoxel-wise seed-based functional connectivity of the thalamus used the Functional Magnetic Resonance Imaging Expert Analysis Tool (FEAT) in FMRIB's Software Library (FSL). Inter-group differences and relationships between clinical scores and functional connectivity for each group were assessed using a general linear model with age and gender as covariates.ResultsStructural AnalysisTVs for all PSP subgroups were smaller than controls. No differences between PSP subgroups were detected. There was evidence for a relationship between TVs for the entire PSP group and Revised Addenbrooke's Cognitive Examination (ACER) scores [ß = 0.28, 95% credible interval (CI) = 0.04–0.53]. Subgroup analysis showed evidence for a relationship between ACER scores and TVs in PSP-RS [ß = 0.33, 95% CI = 0.09–0.57] and PSP-cortical [ß = 0.46, 95% CI = 0.12–0.83] phenotypes. A negative influence of TVs on total PSP rating scale scores was found for the PSP cohort a whole [ß = −0.51, 95% CI = −1.00 – −0.02].Functional AnalysisPSP patients as a group showed decreased thalamic functional connectivity in higher cortical regions. Subgroup analysis revealed decreased connectivity in those areas compared to controls but in distinct distributions and magnitude. Increased thalamic connectivity with the middle temporal gyrus correlated with ACER scores for PSP patients as a group and in the PSP-cortical subtype.ConclusionThalamic volume loss is a prominent aspect of PSP and is associated with a wide network of changes in functional connectivity that may be distinct between PSP subtypes. Changes in thalamic structure and function predict clinical severity, particularly in PSP-RS and PSP-cortical subtypes.

0268 Characterization of Neurodegenerative Disorder Subtypes Based on Non-REM Hypertonia and Sleep Spindle Duration

Abstract Introduction Increased non-REM hypertonia (NRH) and decreased sleep spindle-durations were found to be independently associated with patients broadly characterized as presumed Parkinsonian-spectrum disorder [i.e., dementia with Lewy Bodies/Parkinson Disease Dementia (DLB/PDD), Parkinson Disease (PD), progressive supranuclear palsy (PSP), or isolated REM sleep behavior disorder (iRBD)] when compared to subjects with Alzheimer Disease dementia (AD), mild cognitive impairment (MCI) and normal cognition (NC). In this investigation, the NRH and spindle-duration features were combined to determine whether these biomarkers could distinguish neurodegenerative disorder subtypes. Methods This multicenter investigation included analysis of several neurodegenerative disorder patient subtypes including: DLB/PDD (n=16), PD (n=16), iRBD (n=19), PSP (n=13), AD (n=22), MCI (n=35), and NC (n=61). Sleep Profiler (SP) studies were conducted in all participants. NRH was auto-detected based on persistently elevated electromyographic (EMG) power relative to delta, theta, and sigma bands, while spindles were recognized by temporal excursions in alpha and sigma power &amp;gt; 250-milliseconds. With NRH &amp;gt;5% of sleep-time and spindle-duration &amp;lt;1-minute considered abnormal, tallies were compared across neurodegenerative disorder subtypes with Fisher Exact tests. Results Combined SP features of Normal-NRH/normal-SpD were greater in the NC (56%), AD (46%), and MCI (43%) subtypes versus PSP (8%) and DLB/PDD (6%), and when iRBD (21%) was compared to NC (all P&amp;lt;0.05). Abnormal-NRH/abnormal-SpD were more frequent in PSP (85%) and DLB/PDD (75%) subtypes versus iRBD (26%), PD (25%), MCI (11%), AD (9%), and NC (8%)(all P&amp;lt;0.02). Abnormal-NRH/normal-SpD were greater in iRBD (47%) compared to MCI (14%), NC (8%), PSP (8%), DLB/PDD (6%), and AD (5%) subtypes, and in PD (31%) versus NC (all P&amp;lt;0.05). Normal-NRH/abnormal-SpD occurred more often in AD (41%) than iRBD (5%) and PSP (0%)(both P&amp;lt;0.05). Conclusion The combination of NRH and spindle-duration abnormality occurred more frequently in DLB/PDD and PSP subtypes. Abnormal NRH with normal sleep-duration was more frequent in iRBD and PD subtypes. Normal NRH and spindle-duration occurred most often in NC and MCI types. AD exhibited normal NRH with isolated cases of either normal or abnormal spindle-duration. Our preliminary findings suggest that auto-detected sleep biomarkers may aid in the characterization of neurodegenerative disorder subtypes. Larger prospective cohort studies are needed. Support (If Any) NIA grants: R44AG050326, R44AG054256, P30AG62677 and R34AG56639.

Dopamine transporter imaging in progressive supranuclear palsy: Severe but nonspecific to subtypes.

Previous studies with a limited sample size suggested more severe dopaminergic transporter (DAT) lesions in the striatum of progressive supranuclear palsy (PSP) than those in Parkinson's disease (PD) and multiple system atrophy-parkinsonism (MSA-P). However, few studies had taken various subtypes of PSP into consideration, making the reanalysis of DAT imaging in larger PSP cohort with various subtypes in need. To compare the dopaminergic lesion patterns of PSP with MSA-P and PD, and to explore the specific striatal subregional patterns of different PSP subtypes. 11 C-CFT positron emission tomography (PET) imaging was conducted in 83 PSP patients consisting of different subtypes, 61 patients with PD, 41 patients with MSA-P, and 43 healthy volunteers. Demographic and clinical data were compared by the chi-squared test or one-way analysis of variance. A generalized linear model was used to examine intergroup differences in tracer uptake values after adjusting for age, disease duration, and disease severity. Areas under the receiver operating characteristic curve were calculated to assess the diagnostic accuracy of subregional DAT binding patterns. The patients with PSP presented more severe DAT loss in the striatum than in PD and MSA-P, especially in caudate. In PSP, the subregional lesion was still more severe in putamen than in caudate, similar to that in PD and MSA-P. Among detailed subtypes, no significant difference was detected. The dopaminergic lesions were more severe in PSP, and no difference was detected among subtypes.

Protracted course progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP-P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD). Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology. We identified four cases with long (&gt;10-15years) or very long (&gt;15years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP-P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP-RS) and Stage 4/6 (PSP-P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309-C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G-allele. We propose a protracted course subtype of PSP (PC-PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309-C allele may influence the protracted disease course. Crystallizing the concept of PC-PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation.

Differential Diagnosis of Rare Subtypes of Progressive Supranuclear Palsy and PSP-Like Syndromes-Infrequent Manifestations of the Most Common Form of Atypical Parkinsonism.

Presently, there is increasing interest in rare PSP (progressive supranuclear palsy) variants, including PSP-PGF (PSP-progressive gait freezing), PSP-PI (PSP-postural instability), PSP-OM (PSP-ocular motor dysfunction), PSP-C (PSP-predominant cerebellar ataxia), PSP-CBS (PSP-corticobasal syndrome), PSP-SL (PSP-speech/language disorders), and PSP-PLS (PSP-primary lateral sclerosis). Diagnosis of these subtypes is usually based on clinical symptoms, thus thorough examination with anamnesis remains a major challenge for clinicians. The individual phenotypes often show great similarity to various neurodegenerative diseases and other genetic, autoimmune, or infectious disorders, manifesting as PSP-mimicking syndromes. At the current stage of knowledge, it is not possible to isolate a specific marker to make a definite ante-mortem diagnosis. The purpose of this review is to discuss recent developments in rare PSP phenotypes and PSP-like syndromes.

18F-FDG PET/CT and 99mTc-TRODAT Scan Findings in the Variants of Progressive Supranuclear Palsy and Correlation With Clinical Findings.

The aim of this study is to elucidate the patterns of characteristic hypometabolism on 18F-Fluoro Deoxy-glucose (18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) in the variants of Progressive supranuclear palsy (PSP) and its correlation with their core clinical features. A retrospective analysis of 88 subjects with clinically suspected PSP was done. An institutional informed consent to participate in the study was taken from all the subjects. All the subjects had undergone a prior 99mTechnetium labeled Tropane derivative of dopamine transporter Single Photon Emission Computed Tomography (99mTc TRODAT-1 SPECT) study and had abnormal scans to confirm degenerative parkinsonism. The subjects were clinically examined by the neurologists using the Progressive Supranuclear Palsy Rating Scale proposed by the Movement Disorder Society and were further clinically segregated into eight subtypes. All the included subjects further underwent a detailed clinical analysis to obtain their individual Schwab and England activities of daily living scale and Modified Hoehn and Yahr staging by a neurologist. All the subjects underwent 18F-FDG PET/CT scan after adequate preparation. The scans were analyzed both qualitatively (visually) and quantitatively using Statistical Parametric Mapping. The frontal, limbic, and sensorimotor cortices represented the common areas of hypometabolism among all the subtypes of PSP. The subcortical regions showing the most significant hypometabolism were the thalami, mid-brain, nucleus accumbens, caudate, globus pallidus, and putamen in descending order. Multiple cortical and subcortical regions of hypometabolism were identified in different subtypes of PSP. The characteristic patterns of hypometabolism observed in the different subgroups were more apparent on quantification and based on visual analysis alone, it may not be possible to differentiate the different subtypes of PSP. A good correlation was seen between some of the core clinical features and hypometabolic clusters.

Quantitative evaluation of oculomotor disturbances in progressive supranuclear palsy

ObjectivesTo explore and quantify systematically the ocular abnormal movements present in progressive supranuclear palsy (PSP) from the early stages, to assess the ability of this standardized examination in the differential diagnosis of PSP from Parkinson's disease (PD), and to compare in more detail oculomotor disturbances between PSP variants. MethodsSixty-five consecutive PSP patients with <5 years of disease duration diagnosed according to MDS-PSP criteria, 25 PD patients and 25 controls comparable in age, education and disease duration were explored using a bedside battery of tests for the quantitative evaluation of oculomotor dysfunction in clinical practice. Other accepted scales were used for measurement of motor (PSPRS), cognitive (FAB) and behavioral (FBI) impairment. ResultsMeasurement of oculomotor dysfunction significantly differentiated PSP from PD and controls (p < 0.001) and showed high accuracy in the differential diagnosis of early-to-mid stage PSP from PD. PSP-Parkinsonism and PSP-Progressive Gait Freezing phenotypes showed more preserved ocular motor function compared to PSP-Richardson Syndrome, although no differences were found between PSP subtypes in the number of square wave jerks, optokinetic nystagmus defects, degree of apraxia of eyelid opening, or presence of the “Round the Houses” sign. ConclusionsUsing a bedside clinical instrument for quantifying oculomotor disturbances in PSP shows promising potential at differentiating PSP from PD, and it seems able to provide a qualitative and quantitative description of ocular motor function in parkinsonian disorders.

Cognitive and behavioral profile of progressive supranuclear palsy and its phenotypes.

Although several progressive supranuclear palsy (PSP) phenotypes have recently been described, studies identifying cognitive and neuropsychiatric differences between them are lacking. An extensive battery of cognitive and behavioural assessments was administered to 63 PSP patients, 25 PD patients with similar sociodemographic characteristics, and 25 healthy controls. We analysed differences in phenomenology, frequency and severity of cognitive and neuropsychiatric symptoms between PSP, PD and HC, and between PSP subtypes. Regarding phenotypes, 64.6% met criteria for Richardson's syndrome (PSP-RS), 10.7% PSP with predominant Parkinsonism (PSP-P), 10.7% with PSP progressive gait freezing (PSP-PGF), and 10.7% PSP with predominant speech/language disorder (PSP-SL). Impairment was more severe in the PSP group than in the PD and HC groups regarding motor scores, cognitive testing and neuropsychiatric scales. Cognitive testing did not clearly differentiate between PSP phenotypes, but PSP-RS and PSP-SL appeared to have more cognitive impairment than PSP-PGF and PSP-P, mainly due to an increased impairment in frontal executive domains. Regarding neuropsychiatric disturbances, no specific behavior was more common in any of the PSP subtypes. Motor deficits delineate the phenotypes included in currently accepted MDS-PSP criteria. Cognition and behavioural disturbances are common in PSP and allow us to distinguish this disorder from other neurological diseases, but they do not differentiate between PSP phenotypes.

Deciphering the saccade velocity profile of progressive supranuclear palsy: A sign of latent cerebellar/brainstem dysfunction?

ObjectiveTo study whether the velocity profile of horizontal saccades could be used as an indicator of brainstem and cerebellar output dysfunction, depending on progressive supranuclear palsy (PSP) subtype. MethodsWe compared the velocity profiles in 32 PSP patients of various subtypes with 38 age-matched normal subjects, including Richardson syndrome (RS), PSP-parkinsonism (PSPp), and pure akinesia (PAGF), and cerebellar subtypes of PSP (PSPc). ResultsPSP patients showed reduced peak velocity along with increased duration, especially in the deceleration phase. This alteration was more prominent for larger target eccentricities (20–30 degrees), and correlated with disease severity. The changes were most pronounced in PSPc patients, with irregular increases and decreases in velocity profile, followed by RS patients, whereas the change was smaller in PSPp and normal in PAGF patients. ConclusionsSaccade velocity profile can be an indicator of brainstem and/or cerebellar output. Altered velocity profile of PSP patients may reflect the pathology in the brainstem, but may also reflect cerebellar dysfunction, most prominently in PSPc. SignificanceSaccade velocity profile may be used as an indicator of latent cerebellar/brainstem dysfunction.

Subtypes of PSP and Prognosis: A Retrospective Analysis.

Background:Progressive supranuclear palsy (PSP) is a clinically heterogeneous disease characterized by supranuclear gaze palsy and varying combinations of Parkinsonism, gait disturbances, postural instability, and fronto-limbic cognitive dysfunction. A major challenge in clinical diagnosis is the existence of subtypes whose clinical features overlap with those of other Parkinsonian disorders.Objectives:To categorize patients of PSP into its using the recently proposed movement disorder society criteria (2017) and to determine the prognosis of the PSP subtypes.Methods:Demographic and clinical data of patients diagnosed with PSP over a 21 year period were collected by review of medical records and categorized into its subtypes. Subtype prognosis was assessed from the interval between disease onset and attainment of the first of 5 clinical disability milestones namely wheelchair dependency, unintelligible speech, severe dysphagia, severe cognitive impairment, and urinary catheterization.Results:When categorized into subtypes, out of the 334 patients with PSP, PSP-RS predominated (72%), followed by PSP-parkinsonism (PSP-P) (13.5%), PSP-corticobasal syndrome (PSP-CBS) (5.1%), PSP-frontal (PSP-F) (4.2%), PSP-progressive gait freezing (PSP-PGF) (4.2%), PSP-postural instability (PSP-PI) (0.6%), and PSP-speech/language (PSP-SL) (0.3%). PSP-P reaches the milestones of wheelchair dependency, unintelligible speech, and dysphagia later than other subtypes.Conclusion:PSP-RS was the commonest and PSP-OM the rarest PSP subtype in our retrospective PSP cohort analysis. PSP-P had a better prognosis than all other subtypes of PSP. A large proportion of these cases would remain unclassified using NINDS-SPSP (1996) criteria.

Associations Between Amantadine Usage, Gait, and Cognition in PSP: A post-hoc Analysis of the Davunetide Trial.

Introduction: Amantadine anecdotally improves gait in progressive supranuclear palsy (PSP) but definitive data is lacking. We investigated associations between amantadine usage, gait, cognition, and activities of daily living in 310 subjects with PSP using data from the davunetide trial.Method: We compared baseline demographics, PSP Rating Scale (PSPRS), Repeat Battery for the Assessment of Neuropsychological Status (RBANS), and Schwab and England Activities of Daily Living (SEADL) scores between subjects taking vs. not taking amantadine using chi-square tests for categorical variables and independent sample t-tests for continuous variables. Using the general linear model (GLM), we tested whether group status predicted total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, and SEADL before and after the 52-weeks follow-up.Results: Subjects taking vs. not taking amantadine were similar at baseline, except subjects taking amantadine had a higher Clinical Global Impression (CGI) Score (p = 0.01). However, the CGI change score did not differ between groups at week 52 (p = 0.10). Using GLM models (controlling for covariates), we found that subjects taking vs. not taking amantadine did not significantly predict total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, or SEADL at baseline, week 52, or the change score between baseline and week 52.Discussion: This post-hoc analysis of the davunetide trial did not find an association between amantadine and gait or cognitive measures in PSP, but was not powered to find such a difference. Future studies should still examine amantadine for symptomatic benefit in multiple PSP subtypes.

Eye movements and association with regional brain atrophy in clinical subtypes of progressive supranuclear palsy.

To investigate oculomotor impairment in subtypes of progressive supranuclear palsy (PSP) and its associations with clinical features and regional brain volumes in PSP. We compared the video-oculography (VOG) findings of 123 PSP patients, consisting of 66 PSP-Richardson syndrome (PSP-RS), 28 PSP-parkinsonism (PSP-P), and 29 PSP-progressive gait freezing (PSP-PGF), along with 80 Parkinson's disease (PD) patients. We also investigated the associations of the VOG results with clinical features (disease duration, PSP rating scales [PSPRS] scores for dysphagia and postural stability) in the subtypes of PSP patients and with regional volumes in the brainstem, including the midbrain, pons, medulla, and the superior cerebellar peduncle (SCP), among the patients who had MRI images at the time of VOG (30 PSP). All of the three subtypes of PSP patients showed slower vertical saccades and smooth pursuit than that of the PD patients (adjusted p < 0.05). Among the PSP subtypes, saccadic peak velocity, saccadic accuracy, and pursuit gain were significantly decreased in patients with the PSP-RS compared to those with the PSP-PGF (adjusted p < 0.05). In multiple linear regression model, vertical saccadic velocity, latency, accuracy, and pursuit gain were associated with the PSPRS score for dysphagia (adjusted p < 0.05), and a decrease in vertical saccadic speed and accuracy was associated with SCP atrophy (corrected p < 0.05). This study demonstrated the severity of oculomotor dysfunction in differentiating the subtypes of PSP and its significant relationships with the dysphagia symptom and SCP volume in PSP.

Distribution patterns of tau pathology in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

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.