Browsing by Author "Nennesmo, Inger"

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    Astroglial tracer BU99008 detects multiple binding sites in Alzheimer's disease brain
    (Springer Nature, 2021) Kumar, Amit; Koistinen, Niina A.; Malarte, Mona-Lisa; Nennesmo, Inger; Ingelsson, Martin; Ghetti, Bernardino; Lemoine, Laetitia; Nordberg, Agneta; Pathology and Laboratory Medicine, School of Medicine
    With reactive astrogliosis being established as one of the hallmarks of Alzheimer's disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I2BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site [Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA)] model for BU99008, I2BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher 3H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for 3H-BU99008 than 3H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I2BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.
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    Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease
    (medRxiv, 2023-04-24) Valentino, Rebecca R.; Scotton, William J.; Roemer, Shanu F.; Lashley, Tammaryn; Heckman, Michael G.; Shoai, Maryam; Martinez-Carrasco, Alejandro; Tamvaka, Nicole; Walton, Ronald L.; Baker, Matthew C.; Macpherson, Hannah L.; Real, Raquel; Soto-Beasley, Alexandra I.; Mok, Kin; Revesz, Tamas; Warner, Thomas T.; Jaunmuktane, Zane; Boeve, Bradley F.; Christopher, Elizabeth A.; DeTure, Michael; Duara, Ranjan; Graff-Radford, Neill R.; Josephs, Keith A.; Knopman, David S.; Koga, Shunsuke; Murray, Melissa E.; Lyons, Kelly E.; Pahwa, Rajesh; Parisi, Joseph E.; Petersen, Ronald C.; Whitwell, Jennifer; Grinberg, Lea T.; Miller, Bruce; Schlereth, Athena; Seeley, William W.; Spina, Salvatore; Grossman, Murray; Irwin, David J.; Lee, Edward B.; Suh, EunRan; Trojanowski, John Q.; Van Deerlin, Vivianna M.; Wolk, David A.; Connors, Theresa R.; Dooley, Patrick M.; Frosch, Matthew P.; Oakley, Derek H.; Aldecoa, Iban; Balasa, Mircea; Gelpi, Ellen; Borrego-Écija, Sergi; de Eugenio Huélamo, Rosa Maria; Gascon-Bayarri, Jordi; Sánchez-Valle, Raquel; Sanz-Cartagena, Pilar; Piñol-Ripoll, Gerard; Molina-Porcel, Laura; Bigio, Eileen H.; Flanagan, Margaret E.; Gefen, Tamar; Rogalski, Emily J.; Weintraub, Sandra; Redding-Ochoa, Javier; Chang, Koping; Troncoso, Juan C.; Prokop, Stefan; Newell, Kathy L.; Ghetti, Bernardino; Jones, Matthew; Richardson, Anna; Robinson, Andrew C.; Roncaroli, Federico; Snowden, Julie; Allinson, Kieren; Green, Oliver; Rowe, James B.; Singh, Poonam; Beach, Thomas G.; Serrano, Geidy E.; Flowers, Xena E.; Goldman, James E.; Heaps, Allison C.; Leskinen, Sandra P.; Teich, Andrew F.; Black, Sandra E.; Keith, Julia L.; Masellis, Mario; Bodi, Istvan; King, Andrew; Sarraj, Safa-Al; Troakes, Claire; Halliday, Glenda M.; Hodges, John R.; Kril, Jillian J.; Kwok, John B.; Piguet, Olivier; Gearing, Marla; Arzberger, Thomas; Roeber, Sigrun; Attems, Johannes; Morris, Christopher M.; Thomas, Alan J.; Evers, Bret M.; White, Charles L.; Mechawar, Naguib; Sieben, Anne A.; Cras, Patrick P.; De Vil, Bart B.; De Deyn, Peter Paul P. P.; Duyckaerts, Charles; Le Ber, Isabelle; Seihean, Danielle; Turbant-Leclere, Sabrina; MacKenzie, Ian R.; McLean, Catriona; Cykowski, Matthew D.; Ervin, John F.; Wang, Shih-Hsiu J.; Graff, Caroline; Nennesmo, Inger; Nagra, Rashed M.; Riehl, James; Kovacs, Gabor G.; Giaccone, Giorgio; Nacmias, Benedetta; Neumann, Manuela; Ang, Lee-Cyn; Finger, Elizabeth C.; Blauwendraat, Cornelis; Nalls, Mike A.; Singleton, Andrew B.; Vitale, Dan; Cunha, Cristina; Carvalho, Agostinho; Wszolek, Zbigniew K.; Morris, Huw R.; Rademakers, Rosa; Hardy, John A.; Dickson, Dennis W.; Rohrer, Jonathan D.; Ross, Owen A.; Pathology and Laboratory Medicine, School of Medicine
    Background: Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD. Methods: We established the Pick's disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521). Findings: Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65). Interpretation: The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.
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    Visualization of regional tau deposits using (3)H-THK5117 in Alzheimer brain tissue
    (BioMed Central, 2015-07-02) Lemoine, Laetitia; Saint-Aubert, Laure; Marutle, Amelia; Antoni, Gunnar; Eriksson, Jonas P.; Ghetti, Bernardino; Okamura, Nobuyuki; Nennesmo, Inger; Gillberg, Per-Göran; Nordberg, Agneta; Department of Pathology and Laboratory Medicine, IU School of Medicine
    INTRODUCTION: The accumulation of neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein, starts spreading early in specific regions in the course of Alzheimer's disease (AD), correlating with the progression of memory dysfunction. The non-invasive imaging of tau could therefore facilitate the early diagnosis of AD, differentiate it from other dementing disorders and allow evaluation of tau immunization therapy outcomes. In this study we characterized the in vitro binding properties of THK5117, a tentative radiotracer for positron emission tomography (PET) imaging of tau brain deposits. RESULTS: Saturation and competition binding studies of (3)H-THK5117 in post-mortem AD brain tissue showed the presence of multiple binding sites. THK5117 binding was significantly higher in hippocampal (p < 0.001) and temporal (p < 0.01) tissue homogenates in AD compared to controls. Autoradiography studies with (3)H-THK5117 was performed on large frozen brain sections from three AD cases who had been followed clinically and earlier undergone in vivo (18)F-FDG PET investigations. The three AD cases showed distinct differences in regional THK5117 binding that were also observed in tau immunohistopathology as well as in clinical presentation. A negative correlation between in vivo (18)F-FDG PET and in vitro (3)H-THK5117 autoradiography was observed in two of the three AD cases. CONCLUSIONS: This study supports that new tau PET tracers will provide further understanding on the role of tau pathology in the diversity of the clinical presentation in AD.