Neuropathology of progressive supranuclear palsy after treatment with tilavonemab.
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ABSTRACT:
SUBMITTER: Koga S
PROVIDER: S-EPMC9446286 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
Publications
Neuropathology of progressive supranuclear palsy after treatment with tilavonemab.
Koga Shunsuke S Dickson Dennis W DW Wszolek Zbigniew K ZK
The Lancet. Neurology 20211001 10
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Project description:Currently [18F]FDDNP is the only PET imaging probe with the ability to visualize hyperphosphorylated tau fibrillar aggregates in living subjects. In this work, we evaluate in vivo [18F]FDDNP labeling of brain neuropathology, primarily tau fibrillar aggregates, in patients with progressive supranuclear palsy (PSP), a human tauopathy usually lacking amyloid-? deposits.Fifteen patients with PSP received [18F]FDDNP PET scanning. [18F]FDDNP distribution volume ratios, in reference to cerebellar gray matter, were determined for cortical and subcortical areas and compared with those of patients with Parkinson's disease with short disease duration, and age-matched control subjects without neurodegenerative disorders.[18F]FDDNP binding was present in subcortical areas (e.g., striatum, thalamus, subthalamic region, midbrain, and cerebellar white matter) regardless of disease severity, with progressive subcortical and cortical involvement as disease severity increased. Brain patterns of [18F]FDDNP binding were entirely consistent with the known pathology distribution for PSP. High midbrain and subthalamic region [18F]FDDNP binding was distinctive for PSP subjects and separated them from controls and patients with Parkinson's disease.These results provide evidence that [18F]FDDNP is a sensitive in vivo PET imaging probe to map and quantify the dynamic regional localization of tau fibrillar aggregates in PSP. Furthermore, [18F]FDDNP PET may provide a tool to detect changes in tau pathology distribution either associated with disease progression or as a treatment biomarker for future tau-specific therapies. Patterns of [18F]FDDNP binding may also be useful in diagnosis early in disease presentation when clinical distinction among neurodegenerative disorders is often difficult.
| S-EPMC3674205 | biostudies-literature
Project description:Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10-5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.
| S-EPMC8043857 | biostudies-literature
Project description:To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within ±100 kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylation levels of associated genes were tested against relevant variants. Quantitative neuropathology endophenotypes were tested for SNP associations in 422 PSP subjects. Brain levels of LRRC37A4 and ARL17B were associated with rs8070723; MOBP with rs1768208 and both ARL17A and ARL17B with rs242557. Expression associations for LRRC37A4 and MOBP were available in an additional 100 PSP subjects. Meta-analysis revealed highly significant associations for PSP risk alleles of rs8070723 and rs1768208 with higher LRRC37A4 and MOBP brain levels, respectively. Methylation levels of one CpG in the 3' region of ARL17B associated with rs242557 and rs8070723. Additionally, methylation levels of an intronic ARL17A CpG associated with rs242557 and that of an intronic MOBP CpG with rs1768208. MAPT and MOBP region risk alleles also associated with higher levels of neuropathology. Strongest associations were observed for rs242557/coiled bodies and tufted astrocytes; and for rs1768208/coiled bodies and tau threads. These findings suggest that PSP variants at MAPT and MOBP loci may confer PSP risk via influencing gene expression and tau neuropathology. MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes. Our findings have implications for the mechanism of action of variants at some of the top PSP risk loci.
| S-EPMC4947429 | biostudies-literature
Project description: Not available
| S-EPMC5209394 | biostudies-literature
Project description:IntroductionThere is growing interest in using patient-reported outcomes as end points in clinical trials, such as the progressive supranuclear palsy quality of life (PSP-QoL) scale. However, this tool has not been widely validated and its correlation with validated motor scales has not been explored. To evaluate the potential utility of using PSP-QoL as an outcome, it is important to examine its relationship with a standard scale used to evaluate neurologic parameters, such as the PSP Rating Scale.MethodsPSP-QoL and PSP Rating Scale scores were gathered from 60 clinically diagnosed PSP patients, including patients with Richardson syndrome PSP (PSP-RS, n = 43) and those with non-RS PSP variants (n = 17). Linear regression analysis adjusted for age, sex, and disease duration was used to evaluate the cross-sectional relationship between the total and subscale scores of the 2 instruments.ResultsAmong 60 PSP patients, there was a significant correlation between total PSP-QoL and PSP Rating Scale scores. The physical and mentation subscales of each instrument also demonstrated significant correlations. Comparisons among PSP subtypes indicated that worsening PSP-QoL Total and Physical subscale scores correlated with worsening PSP Rating Scale gait subscale scores more strongly for the non-RS PSP variants than for PSP-RS.DiscussionThere is a significant association between the total scores and many of the subscale scores of the PSP-QoL and the PSP Rating Scale. Additionally, the relationship between these measures may differ for PSP-RS and non-RS variants. These findings suggest that the PSP-QoL may be useful in clinical trials as a patient-reported outcome measure. Large prospective multicenter studies utilizing the PSP-QoL are necessary to examine its relationship to disease evolution and changes in the PSP Rating Scale.
| S-EPMC8119324 | biostudies-literature
Project description:The cerebrospinal fluid miRNAs expression was markedly altered in the patients with progressive supranuclear palsy and controls.
2021-12-05 | GSE186921 | GEO
Project description:Progressive supranuclear palsy (PSP) is a neurodegenerative syndrome that is clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism and cognitive decline. Pathologically, diagnosis of PSP is based on characteristic features, such as neurofibrillary tangles, neutrophil threads, tau-positive astrocytes and their processes in basal ganglia and brainstem, and the accumulation of 4 repeat tau protein. PSP is generally recognized as a sporadic disorder; however, understanding of genetic background of PSP has been expanding rapidly. Here we review relevant publications to outline the genetics of PSP. Although only small number of familial PSP cases have been reported, the recognition of familial PSP has been increasing. In some familial cases of clinically probable PSP, PSP pathologies were confirmed based on NINDS neuropathological diagnostic criteria. Several mutations in MAPT, the gene that causes a form of familial frontotemporal lobar degeneration with tauopathy, have been identified in both sporadic and familial PSP cases. The H1 haplotype of MAPT is a risk haplotype for PSP, and within H1, a sub-haplotype (H1c) is associated with PSP. A recent genome-wide association study on autopsyproven PSP revealed additional PSP risk alleles in STX6 and EIF2AK3. Several heredodegenerative parkinsonian disorders are referred to as PSP-look-alikes because their clinical phenotype, but not their pathology, mimics PSP. Due to the fast development of genomics and bioinformatics, more genetic factors related to PSP are expected to be discovered. Undoubtedly, these studies will provide a better understanding of the pathogenesis of PSP and clues for developing therapeutic strategies.
| S-EPMC4572662 | biostudies-literature
Project description: Not available
| S-EPMC7011663 | biostudies-literature
Project description:Purpose of reviewProgressive supranuclear palsy (PSP) is a progressive adult-onset neurodegenerative disease. Abnormally, phosphorylated forms of the microtubule-associated protein tau containing four repeat domains (4R-tau) aggregate in neurons. Additionally, increasing evidence suggests that secretion and uptake of fragments of abnormal 4R-tau may play a role in disease progression. This extracellular tau is a natural target for immunotherapy.Recent findingsThree monoclonal antibodies targeting extracellular tau are in clinical stages of development. ABBV-8E12 and BIIB092 were safe in Phase 1, but both Phase two studies recently failed futility analyses. UCB0107 recently reported (in abstract form) Phase 1 safety results, and a Phase 2 study is under consideration. Stem cell therapy and the infusion of plasma are also being explored clinically.SummaryThe likely role of extracellular tau in the progression of PSP makes tau a natural target for targeted immunotherapy. Clinical trials are still in early stages, and although tau immunotherapy has largely been shown to be safe, efficacy has yet to be demonstrated.
| S-EPMC7722007 | biostudies-literature
Project description:IntroductionTremor is thought to be a rare feature of progressive supranuclear palsy (PSP).MethodsWe retrospectively reviewed the database of the CurePSP brain bank at Mayo Clinic Florida to retrieve all available clinical information for PSP patients. All patients underwent a standard neuropathological assessment and an immunohistochemical evaluation for tau and α-synuclein. DNA was genotyped for the MAPT H1/H2 haplotype.ResultsOf the 375 PSP patients identified, 344 had a documented presence or absence of tremor, which included 146 (42%) with tremor, including 29 (20%) with postural/action tremors, 16 (11%) with resting tremor, 7 (5%) with intention tremor, 20 (14%) with a combination of different types of tremor, and 74 (51%) patients who had tremor at some point during their illness, but details were unavailable. The tremor severity of 96% of the patients (54/55) who had this data was minimal to mild. The probability of observing a tremor during a neurological examination during the patient's illness was estimated to be ∼22%. PSP patients with postural/action tremors and PSP patients with resting tremor responded to carbidopa-levodopa therapy more frequently than PSP patients without tremor, although the therapy response was always transient. There were no significant differences in pathological findings between the tremor groups.ConclusionsTremor is an inconspicuous feature of PSP; however, 42% (146/344) of the PSP patients in our study presented some form of tremor. Because there is no curative therapy for PSP, carbidopa/levodopa therapy should be tried for patients with postural, action, and resting tremor.
| S-EPMC4887294 | biostudies-literature