PSP Patients Research Articles

Erythrocytic α-Synuclein in Parkinson’s Disease and Progressive Supranuclear Palsy—A Pilot Study

Background/Objectives: The current research examines the accuracy of α-synuclein in RBCs as a diagnostic biomarker for PD and PSP, despite their distinct molecular etiologies. Methods: We used ELISA to measure total, oligomeric, and p129-α-synuclein levels in erythrocytes from 8 PSP patients, 19 PD patients, and 18 healthy controls (HCs). The classification performances of RBC α-synuclein levels were investigated by receiver operator characteristic (ROC) curve. We also evaluated a possible correlation between RBC α-synuclein level and the biological and clinical features of our cohorts. Results: RBC total α-synuclein was higher in PSP patients compared to both PD patients and HCs, achieving good classification performance (AUC: 0.853) in distinguishing PSP patients from PD patients, with a sensitivity of 100% and a specificity of 70.6%; moreover, the levels of this biomarker positively correlated with disease severity in PSP group. Regarding oligomeric α-synuclein and p129-α-synuclein, the latter was slightly increased in RBCs from PSP patients compared to HCs, but no correlations were detected. Conclusions: Although these findings need to be confirmed in larger studies, our pilot work suggests that RBC total α-synuclein may represent a potential molecular biomarker for the differential diagnosis and clinical staging of PSP.

Abnormal Structural–Functional Coupling and MRI Alterations of Brain Network Topology in Progressive Supranuclear Palsy

BackgroundProgressive supranuclear palsy (PSP) can cause structural and functional brain reconstruction. There is a lack of knowledge about the consistency between structural–functional (S–F) connection networks in PSP, despite growing evidence of anomalies in various single brain network parameters.PurposeTo study the changes in the structural and functional networks of PSP, network's topological properties including degree, and the consistency of S–F coupling. The relationship with clinical scales was examined including the assessment of PSP severity, and so on.Study TypeRetrospective.SubjectsA total of 51 PSP patients (70.04 ± 7.46, 25 females) and 101 healthy controls (64.58 ± 8.84, 58 females).Field Strength/Sequence3‐T, resting‐state functional MRI, diffusion tensor imaging, and T1‐weighted images.AssessmentA graph‐theoretic approach was used to evaluate structural and functional network topology metrics. We used the S–F coupling changes to explore the consistency of structural and functional networks.Statistical TestsIndependent samples t tests were employed for continuous variables, χ2 tests were used for categorical variables. For network analysis, two‐sample t tests was used and implied an false discovery rate (FDR) correction. Pearson correlation analysis was used to explore the correlations. A P‐value <0.05 was considered statistically significant.ResultsPSP showed variations within and between modules. Specifically, PSP had decreased network properties changes (t = −2.0136; t = 2.5409; t = −2.5338; t = −2.4296; t = −2.5338; t = 2.8079). PSP showed a lower coupling in the thalamus and left putamen and a higher coupling in the visual, somatomotor, dorsal attention, and ventral attention network. S–F coupling was related to the number of network connections (r = 0.32, r = 0.22) and information transmission efficiency (r = 0.55, r = 0.28). S–F coupling was related to basic academic ability (r = 0.39) and disinhibition (r = 0.49).Data ConclusionPSP may show abnormal S–F coupling and intramodular and intermodular connectome in the structural and functional networks.Level of Evidence3Technical EfficacyStage 3

Clinical and molecular predictors of survival among atypical parkinsonian syndromes in a North African tertiary referral center

IntroductionAtypical Parkinsonian Syndromes(APS) are challenging neurodegenerative disorders due to their heterogeneous phenotypic overlaps.So far,there are no validated biomarkers that can accurately predict disease progression,and survival studies were highly different and contradictory. AimTo investigate clinical and molecular survival factors among Tunisian APS patients. MethodsA retrospective study included Tunisian APS-patients.Using clinical and molecular parameters,survival was explored by Kaplan-Meier analysis. ResultsWe included 409-APS patients divided into 166-DLB,112-PSP,81-MSA and 50-CBS.Survival rate was similar in synucleinopathies, while it differed in tauopathies,being shorter in PSP compared to CBS.Median survival in DLB was different according to gender(p = 0.0048),early parkinsonism and cognitive disorders. Among MSA, prognosis was worse in MSA-C-patients(p = 0.012) and those with stridor(p = 0.0049),oculomotor and neuropsychiatric disorders. For tauopathies, survival was shorter in PSP-RS(p = 0.027),cerebellar phenotype, those with tremor and swallowing problems at onset, early parkinsonism and memory impairment. For CBS,prognosis was worse in patients with tremor,swallowing and cognitive problems.Significant differences were noted in terms of survival across APS non-carriers of APOE-ε4(p < 0.001) as well APS patients carriers of MAPT-H1.PSP patients had lower survival rate according to MAPT haplotype carriage. Moreover, the number of copies had an influence as patients with H1/H2-MAPT profile had better prognosis than those with H1/H1. ConclusionThis study determined survival rates in APS subgroups,which were comparable across synucleinopathies but shorter in PSP and longer in CBS.It also characterized demographic,phenotypic,and genetic profiles identifying more aggressive forms within APS subgroups.These findings address clinical gaps,aiding counseling for patients and families and guiding clinical management.Furthermore,they could facilitate patient stratification in clinical trials where mortality is an outcome measure.

Ethnic background and distribution of clinical phenotypes in patients with probable progressive supranuclear palsy

BackgroundProgressive Supranuclear Palsy (PSP) is a sporadic neurodegenerative disease without a clear geographic prevalence. Cohorts studied in the UK and India showed no higher prevalence of atypical parkinsonism in South Asian patients. We describe the ethnic and racial background of PSP patients in the Greater Toronto Area (GTA), Canada. MethodsA prospective observational study of patients with clinically probable PSP evaluated at the dedicated Rossy PSP program. Demographic and clinical data were collected at baseline including PSP phenotype. Results were compared with the latest demographic information from the greater Toronto area. ResultsOf the 197 patients screened, 135 had probable PSP and resided within the GTA. The mean age at visit was 71.1 years, disease duration 4.4 years, and disease severity moderate. Compared to our catchment area, there was a higher proportion of patients with a South Asian origin and a lower proportion of patients from East and Southeastern Asia and Africa. A secondary analysis using population census data limited to individuals greater than 65 confirmed the significantly higher representation of South Asians in our clinic but found no differences for other racial and ethnic origins. ConclusionEvaluation of this Toronto cohort found a greater than expected proportion of affected individuals with South Asian ethnic and racial origin. Despite limitations, our results suggest the possibility of a racial and ethnic predisposition to PSP. Further studies are needed to confirm and to address potential associated risk factors, and genome-environmental interactions.

Simple aspiration for spontaneous pneumothorax in adults: A systematic review and meta-analysis of randomized controlled trials

BackgroundSpontaneous pneumothorax (SP) is a widespread clinical entity, and methods of managing adult SP remain controversial. The aim of this meta-analysis was to further determine the clinical efficacy and safety of simple aspiration (SA) in comparison to intercostal tube drainage (ITD) during the management of adult SP. MethodsEMBASE, Medline and the Cochrane Central Register of Controlled Trials via Ovid SP were searched (to June 2023) to identify randomized controlled trials (RCT) that reported outcomes of interest after comparing SA with ITD for the management of adult SP. ResultsThe search strategy yielded 1447 citations, of which 10 RCTs enrolling 1044 subjects were included. Compared with the ITD group, the SA group had a significantly lower the initial success rate of the procedure for the management of SP (OR 0.63, 95% CI [0.47–0.86]; P = 0.004). Moreover, SA was associated with a decreased duration of hospitalization (mean difference-2.05 days, 95% CI [−2.66 – −1.44]; P < 0.001) and a decreased need for operation (P = 0.03). For frequently reported adverse events such as subcutaneous emphysema (P = 0.32), bleeding (P = 0.0.26) and wound infection (P = 0.07), no significant difference between the SA and ITD groups was found. There was no significant difference for other outcomes. Subgroup analysis found that there was no significant difference between SA and ITD in terms of the initial success rate, 1-week success rate or any type of adverse event for PSP patients. ConclusionsIn the management of adult SP, the use of SA decreased the initial success rate but also decreased the duration of hospitalization and the need for operation compared with ITD. The incidence of adverse events did not differ between the two approaches.The research plan was registered at PROSPERO, and the registration number was CRD42023436770.

A novel MAPT variant (E342K) as a cause of familial progressive supranuclear palsy.

MAPT variants are a known cause of frontotemporal dementia and Parkinsonian syndrome, of which progressive supranuclear palsy syndrome (PSP) is a rare manifestation. To report a novel MAPT variant in a PSP pedigree with autosomal dominant inheritance pattern, and to produce a literature review of PSP patients with MAPT variants. A comprehensive clinical, genetic, and molecular neuroimaging investigation was conducted on a 61 years-old female proband diagnosed with PSP. We also collected the clinical presentation data and history of the patient's pedigree, and performed further genetic analysis of 4 relatives, from two generations, with and without symptoms. The proband exhibited typical clinical manifestation of PSP. A cranial MRI revealed midbrain atrophy, and an FDG-PET scan suggested hypo-metabolic changes in caudate nucleus, left prefrontal lobe, both temporal poles, and midbrain. 18F-florzolo-tau-PET revealed tau-protein deposits in the thalamus and brainstem bilaterally. A gene test by whole-exome sequencing identified a novel MAPT variant [NM_005910.6, exon 11, c.1024G > A (p.E342K)], and the same variant was also identified in one affected relative and one asymptomatic relative, a probable pre-symptomatic carrier. The PSP pedigree caused by the novel MAPT (E342K) variant, expanded the mutational spectrum of MAPT.

Diagnostic Challenges in Progressive Supranuclear Palsy: Early Identification and Mimics

AbstractBackgroundProgressive supranuclear palsy (PSP) is an often‐undiagnosed neurodegenerative disorder. There are often delays in diagnosing PSP.MethodRetrospective chart review of all newly diagnosed PSP patients referred to an outpatient clinic. We conducted a review of all initial/new PSP cases in our geriatric clinic. The most common preliminary diagnosis the patients had been given included was idiopathic Parkinson’s disease. Other common diagnoses were vascular Parkinson’s, frontal lobe dementia, psychotic depression and late life psychosis.Clinical records with the subjective accounts, cognitive assessments and brain imaging reports of 23 PSP patients were reviewed.ResultsThe most common cognitive deficits were visuospatial changes (100%), semantic fluency deficits (80.4%), dysexecutive function. Sleep disruption with insomnia with intermittent awakening was also commonly reported.A propensity for falls and multiple falls were also reported. The interval from the onset of symptoms and initial presentation to a clinical provider to diagnosis ranged from 1 ‐ 7 years.ConclusionA high index of suspicion and recognition that PSP might not be as uncommon as previously thought is needed. A timely diagnosis and recognition of the various cognitive and behavioral changes is important.

The contribution of Oculomotor and Motor Deficits in The Assessment of Executive Function in Progressive Supranuclear Palsy Patients

AbstractBackgroundProgressive supranuclear palsy (PSP) was first described in 1964 and is associated with motor, oculomotor, and cognitive deficits. Cognitive assessments often assume intact physical function. Some tests like The Trail Making Test (TMT), a measure of executive function may be impacted by oculomotor and motor impairments. Our aim was to investigate the impact of oculomotor impairments and arm dysfunction on the TMT.Method71 patients from the Rossy PSP Center that met criteria for probable PSP and underwent a neuropsychological test battery, the Toronto Cognitive Assessment (TorCA), were included. Data from the following tests and assessments were used for this study: TMT A and B time, digit forwards and backwards, verbal and animal fluency, Benson copy, and Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) delayed recall, PSP Rating Scale (PSPRS) total score and its oculomotor subscore, MDS‐Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS part III) subscore of the dominant hand was used to rate the motor impairment. We performed spearman correlations and used false discovery rate test correction for multiple comparisons.ResultThe PSP patients (60.6% male, mean age 71.3+/‐6.61) had mean PSPRS score of 41.5+/‐15, PSPRS‐oculomotor subscore 8.0+/‐3, and MDS‐UPDRS III subscore dominant hand 6.5+/‐3.3. We found a positive correlation between PSPRS‐oculomotor subscore and TMT A (r = 0.43 p = 0.005) and TMT B (r = 0.35 p = 0.008). We also found negative correlations between PSPRS‐oculomotor subscore and digits backward (r = ‐0.39 p = 0.005), Benson copy (r = ‐0.39 p = 0.005), CERAD delayed recall (r = ‐0.29 p = 0.034), and animal fluency (r = ‐0.44 p = 0.004). No tests were related to MDS‐UPDRS part III subscore of the dominant hand.ConclusionOculomotor but not motor function affect TMT A and B. However, oculomotor function also relates to other executive and non‐executive tests that do not require visual scanning. Although important to factor in physical deficits when doing cognitive assessments, the TMT appears to be a reliable test for assessing cognitive function in patients with PSP who can perform the test.

Effect of AZP2006, a new treatment for Alzheimer’s Disease and Progressive Supranuclear Palsy, in the Restoration of Lysosomal Homeostasis via the Progranulin‐Prosaposin Axis

AbstractBackgroundProgranulin (PGRN) is a secreted pleiotropic growth factor primarily expressed in neurons and microglia that regulates neuroinflammation, neurite branching and outgrowth. PGRN has been identified as a Cathepsin D chaperone, suggesting a role in lysosomal proteolysis. PGRN together with Prosaposin (PSAP) have been proved to be physiologically involved in lysosomal lipid catabolism. PSAP physically interacts with PGRN and facilitates glycosphingolipid degradation upon lysosomal processing, serving as activators of various lysosomal lipases. Thus, PGRN and PSAP play an essential role in the regulation of lysosomal homeostasis. Reduced lysosomal protein levels and activity, as well as accumulation of toxic proteins, have been observed in age‐dependent neurodegenerative diseases. The impact of the disturbance of the PGRN‐PSAP axis in these diseases is not yet fully understood.AZP2006 (INN: Ezeprogind) is a small molecule currently under development for the treatment of Progressive Supranuclear Palsy (PSP, Ph2a completed) and Alzheimer’s Disease (AD). AZP2006 was proved to protect neurons, to increase synaptogenesis and to reduce neuroinflammation in different models of proteinopathies. Importantly, its neuroprotective properties were fully abolished in absence of PGRN or PSAP. Although its exact mode of action (MOA) is still unclear, AZP2006 has been proved to target lysosomes and bind the complex PGRN‐PSAP. Considering this information, the AZP2006 lysosomal MOA was further investigated.MethodAged (18mo) C57Bl6 mice receiving Aβ1‐42 oligomers bilaterally injected into the CA1 area of the hippocampus, were orally treated (gavage) with AZP2006 (1 or 2mg/kg/day) for 22 days. At the end of the treatment, the brain, CSF and plasma of the animals were collected. Lysosomal markers were investigated (LAMP‐2, LC‐3b, PGRN, PSAP, α‐Syn and glycosphingolipids contents). Histological analysis of the CA1 hippocampal area was performed (LAMP‐2, LC‐3b and α‐Syn in neurons and microglial cells). In addition, plasma and CSF samples of PSP patients generated from PSP Ph2a were analyzed.ResultAZP2006 displayed beneficial effects in the Ab1‐42 oligomers injured aged mice. AZP2006 was able to correct the lysosomal dysfunction and to restore the lysosomal homeostasis.ConclusionAZP2006 represents an original therapeutic approach to protect the PGRN‐PSAP balance that is fundamental for the neuron health.

The impact of neuropsychiatric symptoms in in PSP. An overview of quality of life and functionality

AbstractBackgroundProgressive supranuclear paralysis (PSP) is an atypical parkinsonian disorder associated with oculomotor features, motor disturbances, postural instability along with cognitive problems and neuropsychiatric symptoms. Functional impairment and quality of life (QOL) are often related to the motor symptoms. Our aim was to investigate the contribution of neuropsychiatric symptoms such as depression, anxiety and sleep disturbance to functionality and QOL.MethodWe used data from 69 patients meeting criteria for probable PSP from the Rossy PSP Centre. Neuropsychiatric symptoms, severity and functionality were examined using validated rating scales including the Hamilton Anxiety Rating Scale (HAM‐A) for anxiety, Geriatric Depression Scale (GDS) for depression, Epworth sleepiness scale (ESS) for sleep and Neuropsychiatry Inventory (NPI) total scores. To examine function, we used the Schwab and England Activities of Daily Living Scale (SEADL), severity of disease we used PSP rating scale and for QOL the (EQ‐5D‐5L). Cognition was examined using the Montreal Cognitive Assessment (MOCA). We investigated the relationships between neuropsychiatric symptoms and function and QOL using Pearson correlations controlling for multiple comparisons with false discovery test.ResultIn our sample (37.7% female, mean age 71.2+/‐ 6.5) 26.9% had depression, 13% had anxiety, 97.3% had scores compatible with cognitive impairment. Mean QOL‐EQ‐5D‐5L score was 50.4 +/‐ 25.3, mean PSP‐RS 39.5 +/‐ 12.7. Subgroups were made for QOL and functionality analysis. We found negative correlations between SEADL and HAM‐A (r ‐0.32 p = 0.01), and GDS (r ‐0.32 p = 0.01); between QOL‐EQ‐5D‐5L and GDS (r‐0.51 p = 0.014) and HAM‐A (r‐0.49 p = 0.014). Positive correlations were found between SEADL and QOL‐EQ‐5D‐5L (r = 0.61 p = 0.005) and between PSP‐RS and ESS (r 0.35 p = 0.004). The SEADL and PSP‐RS were negatively correlated (r‐0.39 p = 0.002).ConclusionConsistent with apriori hypotheses we found anxiety, depression and PSP‐RS are related to function as measured by the SEADL and quality of life of PSP patients. Sleep disturbance was related to PSP‐RS. These results emphasize the importance of comprehensive evaluations to better capture the multi‐faceted impairments seen in PSP that have a meaningful impact on the patient’s life.

AZP2006, a New Promising Treatment for Progressive Supranuclear Palsy patients. Phase 2a Study Assessing Tolerability, Safety and Pharmacokinetics. Effect on Biomarkers and Clinical Readouts

AbstractBackgroundProgressive Supranuclear Palsy (PSP) is a rare progressive, fatal neurodegenerative 4‐repeat tauopathy. AZP2006 (INN: Ezeprogind) is a first‐in‐class disease‐modifying oral small molecule acting via its strong binding to the complex Progranulin (PGRN) / Prosaposin (PSAP), able to increase the circulating contents of PGRN (plasma and brain) in non‐clinical models. Preclinically, AZP2006 promotes neuron survival, synaptic function, decreases Tau hyperphosphorylation and reduces neuroinflammation (in vitro and in vivo models of Alzheimer’s disease, PSP and Parkinson’s disease). In healthy volunteers Phase 1 studies, AZP2006 was well tolerated with a good safety profile.MethodAZP2006 safety, tolerability and pharmacokinetic profiles in plasma, whole blood, and CSF were investigated in a randomized, double‐blind, placebo‐controlled, parallel group study comparing 2 doses of AZP2006 (60 mg once daily during the 12‐week treatment period and 80 mg once daily for 10 days followed by 50 mg once daily) with placebo in 36 men and women aged ≥40 years and ≤80 years diagnosed with probable or possible PSP. Patients were observed for an additional 12‐week follow‐up period (NCT04008355).In secondary objectives, CSF biomarkers including PGRN for the target engagement and markers of neurodegeneration (NfL, phospho‐tau T181) as well as markers of neuroinflammation (sTREM2, interleukins, etc.) were quantified. In addition, exploratory efficacy objectives evaluating clinical endpoints (PSP‐RS total, PSP Gait, PSP Ocular, CGI‐ds, Schwab and England ADL) were investigated.ResultAZP2006 was safe and well tolerated; no related SAEs were reported. PK profile confirmed the long AZP2006 half‐life (as predicted in a prior popPK model). High brain penetrance was observed and AZP2006 CSF expected levels were achieved. In addition, the target engagement was confirmed by significant increase (vs baseline) of PGRN plasma levels. A PD‐PK analysis is planned.ConclusionAZP2006 treatment showed promising effects after a 3‐month‐treatment. Considering these promising results, an open‐labelled extension (OLE) was started (60 mg daily) in France. In addition, a larger Phase 2b/3 study in PSP patients testing AZP2006 efficacy over 12‐month‐treatment is under preparation.

The clinical application value of brain 18F-FDG PET/CT in the diagnostics of Parkinsonian syndromes

Objective: To analyze the PET/CT imaging features of fluoride 18F-fluorodeoxyglucose (18F-FDG) in patients with various types of Parkinson's syndrome (PS), and to establish a "diagnostic tree" model of 18F-FDG PET/CT for PS. Methods: Data of patients with Parkinson's disease (PD), patients with multiple system atrophy cerebellar type (MSA-C), and patients with multiple system atrophy Parkinson's type (MSA-P)admitted to the Neurology Department of Huashan Hospital affiliated to Fudan University from January 2019 to December 2021. 18F-FDG PET/CT examination was conducted in all patients. Clinical and follow-up data was collected to determine clinical diagnosis. The specific patterns of brain glucose metabolism in patients with various types of Parkinsonism were observed and their utility in the differential diagnosis of the disease was analyzed. 18F-FDG PET/CT imaging"diagnostic tree"model was established and its value in the differential diagnosis of Parkinsonism was verified. Results: A total of 320 patients, 187 males and 133 females, aged (62±9) years, were enrolled in our study, including 80 PD, 90 PSP, 114 MSA-C and 36 MSA-P patients. The differential diagnostic features of cerebral glucose metabolism of Parkinsonism were as follows: the metabolism of putamen increased in PD patients, the metabolism of caudate nucleus, thalamus, midbrain, and frontal lobe decreased in PSP patients, the metabolism of cerebellum decreased in MSA-C patients, and the metabolism of putamen and cerebellum decreased in MSA-P patients. The sensitivity and specificity of the"diagnostic tree"model are 88.75% and 91.25% for PD diagnosis, 54.44% and 96.96% for PSP diagnosis, 87.72% and 86.41% for MSA-C diagnosis, and 55.56% and 91.55% for MSA-P diagnosis, respectively. It could correctly classify 75%(240/320) of patients. Conclusions: Characteristic metabolism patterns of brain in 18F-FDG PET/CT imaging is significant for the differential diagnosis of PD, PSP, MSA-C and MSA-P. The"diagnostic tree"model is valuable for clinical diagnosis.

Proof-of-concept for characterization of neurodegenerative disorders utilizing two non-REM sleep biomarkers.

This proof-of-concept study aimed to determine whether the combined features of two non-rapid eye movement (NREM) sleep biomarkers acquired predominantly in-home could characterize different neurodegenerative disorders. Sleep spindle duration and non-REM hypertonia (NRH) were evaluated in seven groups including a control group (CG = 61), and participants with isolated REM sleep behavior disorder (iRBD = 19), mild cognitive impairment (MCI = 41), Parkinson disease (PD = 16), Alzheimer disease dementia (ADem = 29), dementia with Lewy Bodies or Parkinson disease dementia (LBD = 19) and progressive supranuclear palsy (PSP = 13). One-way analysis of variance (ANOVA), Mann-Whitney U, intra-class (ICC) and Spearman ranked correlations, Bland-Altman plots and Kappa scores, Chi-square and Fisher exact probability test, and multiple-logistic regression were focused primarily on spindle duration and NRH and the frequencies assigned to the four normal/abnormal spindle duration/NRH combinations. ANOVA identified group differences in age, sleep efficiency, REM, NRH (p < 0.0001) and sleep time (p = 0.015), Spindle duration and NRH each demonstrated good night-to-night reliabilities (ICC = 0.95 and 0.75, Kappa = 0.93 and 0.66, respectively) and together exhibited an association in the PD and LBD groups only (p < 0.01). Abnormal spindle duration was greater in records of PSP (85%) and LBD (84%) patients compared to CG, MCI, PD and ADem (p < 0.025). Abnormal NRH was greater in PSP = 92%, LBD = 79%, and iRBD = 74% compared to MCI = 32%, ADem = 17%, and CG = 16% (p < 0.005).The combination biomarker normal spindle duration/normal NRH was observed most frequently in CG (56%) and MCI (41%). ADem most frequently demonstrated normal spindle duration/normal NRH (45%) and abnormal spindle duration/normal NRH (38%). Normal spindle duration/abnormal NRH was greatest in iRBD = 47%, while abnormal spindle duration/abnormal NRH was predominant in PSP = 85% and LBD = 74%. The NREM sleep biomarkers spindle duration and NRH may be useful in distinguishing patients with different neurodegenerative disorders. Larger prospective cohort studies are needed to determine whether spindle duration and NRH can be combined for prodromal assessment and/or monitoring disease progression.

Tau in Atypical Parkinsonisms: A Meta‐Analysis of in Vivo PET Imaging Findings

AbstractBackgroundProgressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are atypical parkinsonisms (APs) that are classified as tauopathies. Patients with these APs may present with similar early clinical manifestations to Parkinson's disease (PD), but they prove unresponsive to anti‐parkinsonian medications.ObjectiveThe main objective of this meta‐analysis was to compare first‐ and second‐generation tau PET tracer efficacy in patients with the APs to identify potential diagnostic biomarkers.MethodsPubMed and Web of Science were searched between January 1, 1999 and December 31, 2022. We included case–control studies that were published in English and report tau PET tracer binding as mean ± SD in at least one region of interest (ROI). Differences in tau PET binding values were meta‐analyzed using random‐effects meta‐analytic models and subgroup analyses based on ROIs in the statistical programming language R (version 4.2.1).ResultsOverall, 29 studies with 665 patients were included in the final review. [18F]PI‐2620 outperformed first‐generation tracers when comparing PSP‐HC (g = −1.68, 95% CI: −2.05 to −1.30) and CBD‐HC (g = −1.37, 95% CI: −2.25 to −0.49). When comparing PSP‐PD, the first‐generation tracer, [18F]AV‐1451, presented with higher binding to PSP patients (g = −0.80, 95% CI: −1.24 to −0.35).ConclusionsOur results demonstrate the efficacy of [18F]PI‐2620 PET in imaging AP‐tau. These findings contribute towards identifying a diagnostic imaging biomarker for patients with APs. The main limitation of this study was the heterogeneity of the results. Future studies should conduct AP‐PD comparisons with second‐generation tracers to confirm the preliminary results found here.

Waiting impulsivity in progressive supranuclear palsy-Richardson's syndrome.

Waiting impulsivity in progressive supranuclear palsy-Richardson's syndrome (PSP-RS) is difficult to assess, and its regulation is known to involve nucleus accumbens (NAc) subregions. We investigated waiting impulsivity using the "jumping the gun" (JTG) sign, which is defined as premature initiation of clapping before the start signal in the three-clap test and compared clinical features of PSP-RS patients with and without the sign and analyzed neural connectivity and microstructural changes in NAc subregions. A positive JTG sign was defined as the participant starting to clap before the start sign in the three-clap test. We classified participants into the JTG positive (JTG +) and JTG negative (JTG-) groups and compared their clinical features, microstructural changes, and connectivity between NAc subregions using diffusion tension imaging. The NAc was parcellated into core and shell subregions using data-driven connectivity-based methods. Seventy-seven patients with PSP-RS were recruited, and the JTG + group had worse frontal lobe battery (FAB) scores, more frequent falls, and more occurrence of the applause sign than the JTG- group. A logistic regression analysis revealed that FAB scores were associated with a positive JTG sign. The mean fiber density between the right NAc core and right medial orbitofrontal gyrus was higher in the JTG + group than the JTG- group. We show that the JTG sign is a surrogate marker of waiting impulsivity in PSP-RS patients. Our findings enrich the current literature by deepening our understanding of waiting impulsivity in PSP patients and introducing a novel method for its evaluation.

Differentiating between common PSP phenotypes using structural MRI: a machine learning study.

Differentiating Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) from PSP-Parkinsonism (PSP-P) may be extremely challenging. In this study, we aimed to distinguish these two PSP phenotypes using MRI structural data. Sixty-two PSP-RS, 40 PSP-P patients and 33 control subjects were enrolled. All patients underwent brain 3T-MRI; cortical thickness and cortical/subcortical volumes were extracted using Freesurfer on T1-weighted images. We calculated the automated MR Parkinsonism Index (MRPI) and its second version including also the third ventricle width (MRPI 2.0) and tested their classification performance. We also employed a Machine learning (ML) classification approach using two decision tree-based algorithms (eXtreme Gradient Boosting [XGBoost] and Random Forest) with different combinations of structural MRI data in differentiating between PSP phenotypes. MRPI and MRPI 2.0 had AUC of0.88 and 0.81, respectively, in differentiating PSP-RS from PSP-P. ML models demonstrated that the combination of MRPI and volumetric/thickness data was more powerful than each feature alone. The two ML algorithms showed comparable results, and the best ML model in differentiating between PSP phenotypes used XGBoost with a combination of MRPI, cortical thickness and subcortical volumes (AUC 0.93 ± 0.04). Similar performance (AUC 0.93 ± 0.06) was also obtained in a sub-cohort of 59 early PSP patients. The combined use of MRPI and volumetric/thickness data was more accurate than each MRI feature alone in differentiating between PSP-RS and PSP-P. Our study supports the use of structural MRI to improve the early differential diagnosis between common PSP phenotypes, which may be relevant for prognostic implications and patient inclusion in clinical trials.

Longitudinal clinical decline and baseline predictors in progressive supranuclear palsy

IntroductionProgressive supranuclear palsy (PSP) is associated with several clinical variants defined based on ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction, although little is known about how these features progress over time. We aimed to assess the evolution of these core clinical features across variants and assess baseline clinical and neuroimaging predictors of progression. MethodsNinety-three PSP patients were recruited by the Neurodegenerative Research Group, Mayo Clinic, and underwent two visits 1-year apart, with baseline MRI and [18F]flortaucipir PET. We compared baseline and annualized rates of clinical change on the PSP Rating Scale (total, ocular motor, gait/midline scores) and Montreal Cognitive Assessment, across PSP-Richardson's, PSP-Cortical and PSP-Subcortical variants and assessed relationships between rates of change and baseline regional imaging. ResultsOcular motor scores differed across groups at baseline and follow-up, with lowest scores observed in PSP-subcortical, but no differences were observed in rate of change across groups. PSP Rating Scale total and gait/midline scores differed across groups at follow-up and in rates of change, with PSP-subcortical showing the least impairment and slowest progression. Greatest cognitive impairment was observed in PSP-Cortical. Sample size estimates for treatment trials differed across PSP variants. Greater baseline flortaucipir uptake, but not volume, of midbrain and motor cortex correlated with faster rates of clinical decline. ConclusionThe PSP Rating Scale and its subscores might be useful markers for the prognostic stratification of PSP variants. Flortaucipir imaging at baseline may help predict rate of decline.

Mitochondrial dysfunction in models of Progressive Supranuclear Palsy

AbstractBackgroundProgressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease hallmarked by tau pathology in both neurons and astrocytes. Familial forms of PSP are caused by mutations affecting tau (MAPT) while risk factors for sporadic PSP are largely unknown. Mitochondrial function declines during aging and mitochondrial dysfunction is observed in PSP. Generation of reactive oxygen species and mitochondrial dysfunction are thought to directly contribute to the production of tau deposits. Here we interrogated mitochondrial function in astrocytes and neurons derived from induced pluripotent stem cell models of sporadic and familial PSP.MethodsInduced pluripotent stem cells were obtained from healthy controls, patients with sporadic PSP, and PSP patients carrying a MAPT A152T mutation. iPSCs were differentiated into neurons and astrocytes following StemCell Technologies protocols. Mitochondrial function was assessed using the Seahorse XFe96 analyzer. Fluorescent stains were used to determine mitochondrial mass, mitochondrial membrane potential, mitophagy levels, mitochondrial turnover, and mitochondrial calcium levels.ResultsNeurons derived from sporadic PSP and A152T tau patients had decreased mitochondrial respiration, increased mitochondrial superoxide, and increased mitochondrial mass. Astrocytes derived from sporadic PSP patients had increased mitophagy, mitochondrial turnover, mitochondrial calcium, and mitochondrial superoxide. Complex I and Complex IV activity were increased in sporadic PSP derived astrocytes, but in A152T tau astrocytes we observed decreased Complex I activity.ConclusionNeurons and astrocytes derived from PSP patients show changes in mitochondrial function. Alterations are cell type specific and differ between sporadic and familial PSP models. We are working to determine how this contributes to tau pathology.

Efficacy evaluation of a novel vectorized anti‐tau antibody, targeting a C‐terminal phospho‐tau epitope, using systemic dosing of a blood brain barrier penetrant AAV capsid in mouse models of tauopathies.

AbstractBackgroundAnti‐tau immunotherapy has become a promising therapy for Alzheimer’s disease (AD) and tauopathies. With the hypothesis that tau pathology spreads via cell‐to‐cell transmission, including trans‐synaptic propagation, success of anti‐tau immunotherapy relies, in part, on the identification of efficacious antibodies and their delivery to affected or vulnerable brain regions with sufficient or enhanced exposure in the CNS. We have previously demonstrated broad distribution and expression of vectorized anti‐tau antibodies in the mouse brain using a blood brain barrier penetrant capsid, VOY101, administered intravenously (IV).MethodSeveral novel anti‐tau antibodies that met the target profile have been generated and are being evaluated in vivo (Liu et al, submitted as a separated abstract in AAIC 2022).ResultOne of the antibodies discovered, antibody 1, exhibits strong affinity for PHF‐tau, demonstrates specific binding to tau pathology on brain sections of AD and PSP patients, and potently prevents PHF seeding and propagation in vitro and in vivo. This antibody recognizes a phospho‐specific epitope in the C‐terminal region of tau and shows significant reduction of tau pathology in an AD‐PHF induced P301S hippocampal seeding and propagation model. Furthermore, we have vectorized antibody 1 into an AAV expression vector with by BBB penetrant capsid and are evaluating it in two independent mouse models of tauopathy.ConclusionThis gene therapy‐based approach has potential advantages over traditional passive immunization, including 1) continuous expression of antibody in the central nervous system (CNS) after a single gene therapy administration compared to repetitive administrations of high dose of antibody by passive immunotherapy; 2) increased CNS exposure of tau antibody relative to passive immunotherapy; and 3) the potential to target intracellular tau aggregates which are less effectively accessed by passively delivered antibody. These results add to accumulating evidence that systemic dosing of a vectorized anti‐tau antibody using a BBB‐penetrant AAV capsid results in reduced tau pathology and may represent a new single‐dose therapeutic strategy for treating various tauopathies.

Cortical atrophy distinguishes idiopathic normal-pressure hydrocephalus from progressive supranuclear palsy: A machine learning approach

IntroductionProgressive supranuclear palsy (PSP) and idiopathic normal pressure hydrocephalus (iNPH) share several clinical and radiological features, making the differential diagnosis challenging. In this study, we aimed to differentiate between these two diseases using a machine learning approach based on cortical thickness and volumetric data. MethodsTwenty-three iNPH patients, 50 PSP patients and 55 control subjects were enrolled. All participants underwent a brain 3T-MRI, and cortical thickness and volumes were extracted using Freesurfer 6 on T1-weighted images and compared among groups. Finally, the performance of a machine learning approach with random forest using the extracted cortical features was investigated to differentiate between iNPH and PSP patients. ResultsiNPH patients showed cortical thinning and volume loss in the frontal lobe, temporal lobe and cingulate cortex, and thickening in the superior parietal gyrus in comparison with controls and PSP patients. PSP patients only showed mild thickness and volume reduction in the frontal lobe, compared to control subjects. Random Forest algorithm distinguished iNPH patients from controls with AUC of 0.96 and from PSP patients with AUC of 0.95, while a lower performance (AUC 0.76) was reached in distinguishing PSP from controls. ConclusionThis study demonstrated a more severe and widespread cortical involvement in iNPH than in PSP, possibly due to the marked lateral ventricular enlargement which characterizes iNPH. A machine learning model using thickness and volumetric data led to accurate differentiation between iNPH and PSP patients, which may help clinicians in the differential diagnosis and in the selection of patients for shunt procedures.