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    Preclinical, phase I, and phase II investigational clinical trials for treatment of progressive supranuclear palsy. Shoeibi Ali,Olfati Nahid,Litvan Irene Expert opinion on investigational drugs INTRODUCTION:Our understanding of the pathological basis of progressive supranuclear palsy (PSP), as the most common atypical parkinsonian syndrome, has greatly increased in recent years and a number of disease-modifying therapies are under evaluation as a result of these advances. AREAS COVERED:In this review, we discuss disease-modifying therapeutic options which are currently under evaluation or have been evaluated in preclinical or clinical trials based on their targeted pathophysiologic process. The pathophysiologic mechanisms are broadly divided into three main categories: genetic mechanisms, abnormal post-translational modifications of tau protein, and transcellular tau spread. EXPERT OPINION:Once the best therapeutic approaches are identified, it is likely that some combination of interventions will need to be evaluated, but this will take time. It is critical to treat patients at early stages, and development of the Movement Disorder Society PSP diagnostic criteria is an important step in this direction. In addition, development of biological biomarkers such as tau PET and further refinement of tau ligands may help both diagnose early and measure disease progression. In the meantime, a comprehensive, personalized interdisciplinary approach to this disease is absolutely necessary. 10.1080/13543784.2018.1460356
    Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype. Jabbari Edwin,Woodside John,Tan Manuela M X,Shoai Maryam,Pittman Alan,Ferrari Raffaele,Mok Kin Y,Zhang David,Reynolds Regina H,de Silva Rohan,Grimm Max-Joseph,Respondek Gesine,Müller Ulrich,Al-Sarraj Safa,Gentleman Stephen M,Lees Andrew J,Warner Thomas T,Hardy John,Revesz Tamas,Höglinger Günter U,Holton Janice L,Ryten Mina,Morris Huw R Annals of neurology OBJECTIVE:The basis for clinical variation related to underlying progressive supranuclear palsy (PSP) pathology is unknown. We performed a genome-wide association study (GWAS) to identify genetic determinants of PSP phenotype. METHODS:Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson syndrome (RS) and non-RS groups. We carried out separate logistic regression GWASs to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS = 367, non-RS = 130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/coexpression patterns of our identified genes and used our data to carry out gene-based association testing. RESULTS:Our lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome-wide significance in our whole cohort analysis (odds ratio = 5.5, 95% confidence interval = 3.2-10.0, p = 1.7 × 10 ). rs564309 is an intronic variant of the tripartite motif-containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene-based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia. INTERPRETATION:Our study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease-modifying therapies. Ann Neurol 2018;84:485-496. 10.1002/ana.25308
    Clinical and neuropathological features of progressive supranuclear palsy in Leucine rich repeat kinase (LRRK2) G2019S mutation carriers. Vilas Dolores,Sharp Madeleine,Gelpi Ellen,Genís David,Marder Karen S,Cortes Etty,Vonsattel Jean-Paul,Tolosa Eduard,Alcalay Roy N Movement disorders : official journal of the Movement Disorder Society 10.1002/mds.27225
    Anti-inflammatory drug use and progressive supranuclear palsy. Marras Connie,Cunningham Christopher R,Hou Jiayi,Proudfoot James,Standaert David G,Juncos Jorge,Riley David,Reich Stephen G,Hall Deborah,Kluger Benzi,Bordelon Yvette,Shprecher David R,Litvan Irene, Parkinsonism & related disorders BACKGROUND:Anti-inflammatory drug use, particularly ibuprofen, has been associated with a lower risk of Parkinson's disease. Microglial activation and inflammatory cytokine expression have been shown to be pathological features of progressive supranuclear palsy. We examined the association between NSAID use and risk of PSP, disease severity and age at onset. METHODS:The ENGENE-PSP multicenter case-control study recruited incident PSP cases who met the NINDS-PSP Society diagnostic criteria and age-, sex- and race-matched controls primarily from the same geographical areas. All subjects underwent standardized interviews to obtain data on demographics, residential history, medication history and lifetime occupational history. NSAID use was specifically queried by telephone interview using a standardized questionnaire. RESULTS:Information was obtained on anti-inflammatory drug exposure in 276 cases and 278 controls. No association was found between NSAID exposure and risk of PSP, age at onset or rate of change of UPDRS motor subscale, PSP Rating Scale or Mattis Dementia Rating Scale scores. This lack of association persisted when NSAID exposure was measured considering any NSAIDs, ibuprofen only, ASA only or non-ibuprofen, non-aspirin NSAIDs. CONCLUSIONS:These results do not suggest an important association between NSAID use and PSP occurrence or expression. Despite the large size of our study, confidence intervals were wide. To rule out small associations, very large sample sizes will be required. 10.1016/j.parkreldis.2017.11.346
    [F]-THK5351 PET Correlates with Topology and Symptom Severity in Progressive Supranuclear Palsy. Brendel Matthias,Schönecker Sonja,Höglinger Günter,Lindner Simon,Havla Joachim,Blautzik Janusch,Sauerbeck Julia,Rohrer Guido,Zach Christian,Vettermann Franziska,Lang Anthony E,Golbe Lawrence,Nübling Georg,Bartenstein Peter,Furukawa Katsutoshi,Ishiki Aiko,Bötzel Kai,Danek Adrian,Okamura Nobuyuki,Levin Johannes,Rominger Axel Frontiers in aging neuroscience Progressive supranuclear palsy (PSP) is a neurodegenerative movement disorder characterized by deposition of fibrillar aggregates of 4R tau-protein in neurons and glial cells of the brain. These deposits are a key neuropathological finding, allowing a diagnosis of "definite PSP," which is usually established post mortem. To date criteria for clinical diagnosis of PSP do not include biomarkers of tau pathology. For intervention trials, it is increasingly important to (i) establish biomarkers for an early diagnosis and (ii) to develop biomarkers that correlate with disease progression of PSP. [F]-THK5351 is a novel PET-ligand that may afford visualization and quantification of tau-related alterations. We investigated binding characteristics of [F]-THK5351 in patients with clinically diagnosed PSP and correlate tracer uptake with clinical findings. Eleven patients (68.4 ± 7.4 year; = 6 female) with probable PSP according to current clinical criteria and nine healthy controls (71.7 ± 7.2 year; = 4 female) underwent [F]-THK5351 PET scanning. Voxel-wise statistical parametric comparison and volume-of-interest based quantification of standardized-uptake-values (SUV) were conducted using the cerebellar cortex as reference region. We correlated disease severity as measured with the help of the PSP Rating Scale (PSPRS) as well as several other clinical parameters with the individual PET findings. By voxel-wise mapping of [F]-THK5351 uptake in the patient group we delineated typical distribution patterns that fit to known tau topology for PSP post mortem. Quantitative analysis indicated the strongest discrimination between PSP patients and healthy controls based on tracer uptake in the midbrain (+35%; = 3.01E-7; Cohen's d: 4.0), followed by the globus pallidus, frontal cortex, and medulla oblongata. Midbrain [F]-THK5351 uptake correlated well with clinical severity as measured by PSPRS ( = 0.66; = 0.026). OCT and MRI delineated PSP patients from healthy controls by use of established discrimination thresholds but only OCT did as well correlate with clinical severity ( = 0.79; = 0.024). Regional [F]-THK5351 binding patterns correlated well with the established post mortem distribution of lesions in PSP and with clinical severity. The contribution of possible MAO-B binding to the [F]-THK5351 signal needs to be further evaluated, but nevertheless [F]-THK5351 PET may still serve as valuable biomarker for diagnosis of PSP. 10.3389/fnagi.2017.00440
    Spatial working memory in Progressive Supranuclear Palsy. Smith Daniel T,Archibald Neil Cortex; a journal devoted to the study of the nervous system and behavior The neural and cognitive mechanisms of spatial working memory are tightly coupled with the systems that control eye-movements but the precise nature of this coupling is not well understood. In particular, there are very few neuropsychological studies that explicitly examine how deficits of oculomotor control affect visuospatial working memory. Here, we examined the link between spatial working memory and the oculomotor system in a sample of patients with Progressive Supranuclear Palsy, a degenerative neurological disease characterised by defective vertical eye-movements but relatively preserved horizontal eye-movements. Consistent with the idea that the oculomotor system plays a critical role in spatial working memory performance, people with PSP had significantly shorter spatial spans when stimuli were presented along the vertical axis compared to the horizontal axis. This effect was not observed in age matched controls. We hypothesise that PSP disrupts a colliculo-parietal feedback loop that contributes to the maintenance of activation in a parietal priority map during the delay period. This result is the first direct neuropsychological evidence for an association between oculomotor function and spatial working memory and is broadly consistent with idea that rehearsal in visuospatial working memory is mediated by an 'oculomotor loop', as proposed by Baddeley (1986). We conclude that optimal spatial working memory performance depends on an intact oculomotor system. 10.1016/j.cortex.2018.07.004
    Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy. Allen Mariet,Wang Xue,Serie Daniel J,Strickland Samantha L,Burgess Jeremy D,Koga Shunsuke,Younkin Curtis S,Nguyen Thuy T,Malphrus Kimberly G,Lincoln Sarah J,Alamprese Melissa,Zhu Kuixi,Chang Rui,Carrasquillo Minerva M,Kouri Naomi,Murray Melissa E,Reddy Joseph S,Funk Cory,Price Nathan D,Golde Todd E,Younkin Steven G,Asmann Yan W,Crook Julia E,Dickson Dennis W,Ertekin-Taner Nilüfer Acta neuropathologica Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies. We provide individual transcript and transcriptional network associations for quantitative oligodendroglial (coiled bodies = CB), neuronal (neurofibrillary tangles = NFT), astrocytic (tufted astrocytes = TA) tau pathology, and tau threads and genomic annotations of these findings. We identified divergent patterns of transcriptional associations for the distinct tau lesions, with the neuronal and astrocytic neuropathologies being the most different. We determined that NFT are positively associated with a brain co-expression network enriched for synaptic and PSP candidate risk genes, whereas TA are positively associated with a microglial gene-enriched immune network. In contrast, TA is negatively associated with synaptic and NFT with immune system transcripts. Our findings have implications for the diverse molecular mechanisms that underlie cell-specific vulnerability and disease risk in PSP. 10.1007/s00401-018-1900-5