Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H et al (2008) Staging of neurofibrillary pathology in Alzheimer's disease: a study of the BrainNet Europe consortium. Brain Pathol 18:484–496. https://doi.org/10.1111/j.1750-3639.2008.00147.x
Article
PubMed
PubMed Central
Google Scholar
Alafuzoff I, Thal DR, Arzberger T, Bogdanovic N, Al-Sarraj S, Bodi I et al (2009) Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe consortium. Acta Neuropathol 117:309–320. https://doi.org/10.1007/s00401-009-0485-4
Article
CAS
PubMed
PubMed Central
Google Scholar
Alzheimer’s Association (2018) Alzheimer's disease facts and figures. Alzheimers Dement. https://doi.org/10.1016/j.jalz.2018.02.001
Amouyel P, Vidal O, Launay JM, Laplanche JL (1994) The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob disease. The French research group on epidemiology of human spongiform encephalopathies. Lancet 344:1315–1318
Article
CAS
Google Scholar
Baiardi S, Abu-Rumeileh S, Rossi M, Zenesini C, Bartoletti-Stella A, Polischi B et al (2018) Antemortem CSF Aβ42/Aβ40 ratio predicts Alzheimer's disease pathology better than Aβ42 in rapidly progressive dementias. Ann Clin Transl Neurol 6:263–273
PubMed
PubMed Central
Google Scholar
Baiardi S, Rossi M, Capellari S, Parchi P (2018) Recent advances in the histo-molecular pathology of human prion disease. Brain Pathol. https://doi.org/10.1111/bpa.12695
Article
Google Scholar
Bishop MT, Will RG, Manson JC (2010) Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties. Proc Natl Acad Sci U S A 107:12005–12010. https://doi.org/10.1073/pnas.1004688107
Article
PubMed
PubMed Central
Google Scholar
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404
Article
Google Scholar
Braak H, Del Tredici K (2015) The preclinical phase of the pathological process underlying sporadic Alzheimer's disease. Brain 138:2814–2833. https://doi.org/10.1093/brain/awv236
Article
PubMed
Google Scholar
Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, Xu Q et al (2004) Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci 24:2527–2534
Article
CAS
Google Scholar
Calero O, Bullido MJ, Clarimón J, Frank-García A, Martínez-Martín P, Lleó A et al (2011) Genetic cross-interaction between APOE and PRNP in sporadic Alzheimer's and Creutzfeldt-Jakob diseases. PLoS One. https://doi.org/10.1371/journal.pone.0022090
Article
CAS
Google Scholar
Cali I, Cohen ML, Haik S, Parchi P, Giaccone G, Collins SJ et al (2018) Iatrogenic Creutzfeldt-Jakob disease with amyloid-β pathology: an international study. Acta Neuropathol Commun 6:5. https://doi.org/10.1186/s40478-017-0503-z
Article
CAS
PubMed
PubMed Central
Google Scholar
Casadei VM, Ferri C, Calabrese E, Grimaldi LM, Franceschi M, Veglia F et al (2001) Prion protein gene polymorphism and Alzheimer's disease: one modulatory trait of cognitive decline? J Neurol Neurosurg Psychiatry 71:279–280
Article
CAS
Google Scholar
Chapman J, Cervenáková L, Petersen RB, Lee HS, Estupinan J, Richardson S et al (1998) APOE in non-Alzheimer amyloidoses: transmissible spongiform encephalopathies. Neurology 51:548–553
Article
CAS
Google Scholar
Chen S, Yadav SP, Surewicz WK (2010) Interaction between human prion protein and amyloid-beta (Abeta) oligomers: role OF N-terminal residues. J Biol Chem 285:26377–26383. https://doi.org/10.1074/jbc.M110.145516
Article
CAS
PubMed
PubMed Central
Google Scholar
Clavaguera F, Hench J, Goedert M, Tolnay M (2015) Prion-like transmission and spreading of tau pathology. Neuropathol Appl Neurobiol 41:47–58. https://doi.org/10.1111/nan.12197
Article
CAS
PubMed
Google Scholar
Combarros O, Sánchez-Guerra M, Llorca J, Alvarez-Arcaya A, Berciano J, Peña N et al (2000) Polymorphism at codon 129 of the prion protein gene is not associated with sporadic AD. Neurology 55:593–395
Article
CAS
Google Scholar
Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I et al (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128:755–766. https://doi.org/10.1007/s00401-014-1349-0
Article
CAS
PubMed
PubMed Central
Google Scholar
Del Bo R, Scarlato M, Ghezzi S, Martinelli-Boneschi F, Fenoglio C, Galimberti G et al (2006) Is M129V of PRNP gene associated with Alzheimer's disease? A case-control study and a meta-analysis. Neurobiol Aging 27:770.e1–770.e5
Google Scholar
Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K et al (2017) Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers. Acta Neuropathol 133:839–856. https://doi.org/10.1007/s00401-017-1685-y
Article
CAS
PubMed
PubMed Central
Google Scholar
Dermaut B, Croes EA, Rademakers R, Van den Broeck M, Cruts M, Hofman A et al (2003) PRNP Val129 homozygosity increases risk for early-onset Alzheimer's disease. Ann Neurol 53:409–412
Article
CAS
Google Scholar
Duyckaerts C, Sazdovitch V, Ando K, Seilhean D, Privat N, Yilmaz Z et al (2018) Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology. Acta Neuropathol 135:201–212. https://doi.org/10.1007/s00401-017-1791-x
Article
CAS
PubMed
Google Scholar
Falker C, Hartmann A, Guett I, Dohler F, Altmeppen H, Betzel C et al (2016) Exosomal cellular prion protein drives fibrillization of amyloid beta and counteracts amyloid beta-mediated neurotoxicity. J Neurochem 137:88–100. https://doi.org/10.1111/jnc.13514
Article
CAS
PubMed
Google Scholar
Farfel JM, Yu L, De Jager PL, Schneider JA, Bennett DA (2016) Association of APOE with tau-tangle pathology with and without β-amyloid. Neurobiol Aging 37:19–25. https://doi.org/10.1016/j.neurobiolaging.2015.09.011
Article
CAS
PubMed
Google Scholar
Ghoshal N, Cali I, Perrin RJ, Josephson SA, Sun N, Gambetti P et al (2009) Codistribution of amyloid beta plaques and spongiform degeneration in familial Creutzfeldt-Jakob disease with the E200K-129M haplotype. Arch Neurol 66:1240–1246. https://doi.org/10.1001/archneurol.2009.224
Article
PubMed
PubMed Central
Google Scholar
Golanska E, Hulas-Bigoszewska K, Rutkiewicz E, Styczynska M, Peplonska B, Barcikowska M et al (2004) Polymorphisms within the prion (PrP) and prion-like protein (Doppel) genes in AD. Neurology 62:313–315
Article
CAS
Google Scholar
Grau-Rivera O, Gelpi E, Nos C, Gaig C, Ferrer I, Saiz A et al (2015) Clinicopathological correlations and concomitant pathologies in rapidly progressive dementia: a brain Bank series. Neurodegener Dis 15:350–360
Article
CAS
Google Scholar
Hainfellner JA, Wanschitz J, Jellinger K, Liberski PP, Gullotta F, Budka H (1998) Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease. Acta Neuropathol 96:116–122
Article
CAS
Google Scholar
Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM et al (2000) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model. Ann Neurol 47:739–747
Article
CAS
Google Scholar
Huzarewich RL, Siemens CG, Booth SA (2010) Application of "omics" to prion biomarker discovery. J Biomed Biotechnol 2010:613504. https://doi.org/10.1155/2010/613504
Article
CAS
PubMed
PubMed Central
Google Scholar
Jansen C, Parchi P, Capellari S, Ibrahim-Verbaas CA, Schuur M, Strammiello R et al (2012) Human prion diseases in the Netherlands (1998-2009): clinical, genetic and molecular aspects. PLoS One 7:e36333. https://doi.org/10.1371/journal.pone.0036333
Article
CAS
PubMed
PubMed Central
Google Scholar
Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J et al (2015) Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 525:247–250. https://doi.org/10.1038/nature15369
Article
CAS
PubMed
Google Scholar
Karran E, De Strooper B (2016) The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem 139(Suppl 2):237–252. https://doi.org/10.1111/jnc.13632
Article
CAS
PubMed
Google Scholar
Kobayashi A, Asano M, Mohri S, Kitamoto T (2009) A traceback phenomenon can reveal the origin of prion infection. Neuropathology 29:619–624. https://doi.org/10.1111/j.1440-1789.2008.00973.x
Article
PubMed
Google Scholar
Kovacs GG, Rahimi J, Ströbel T, Lutz MI, Regelsberger G, Streichenberger N et al (2017) Tau pathology in Creutzfeldt-Jakob disease revisited. Brain Pathol 27:332–344. https://doi.org/10.1111/bpa.12411
Article
CAS
PubMed
Google Scholar
Kovacs GG, Seguin J, Quadrio I, Höftberger R, Kapás I, Streichenberger N et al (2011) Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy. Acta Neuropathol 121:39–57. https://doi.org/10.1007/s00401-010-0713-y
Article
CAS
PubMed
Google Scholar
Krasnianski A, von Ahsen N, Heinemann U, Meissner B, Schulz-Schaeffer WJ, Kretzschmar HA et al (2009) Increased frequency of positive family history of dementia in sporadic CJD. Neurobiol Aging 30:615–621
Article
Google Scholar
Ladogana A, Puopolo M, Croes EA, Budka H, Jarius C et al (2005) Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia, and Canada. Neurology 64:1586–1591. https://doi.org/10.1212/01.WNL.0000160117.56690.B2
Article
CAS
PubMed
Google Scholar
Lattanzio F, Abu-Rumeileh S, Franceschini A, Kai H, Amore G, Poggiolini I et al (2017) Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease: diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and Aβ42 levels. Acta Neuropathol 133:559–578. https://doi.org/10.1007/s00401-017-1683-0
Article
CAS
PubMed
PubMed Central
Google Scholar
Lewis J, Dickson DW (2016) Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol 131:27–48. https://doi.org/10.1007/s00401-015-1507-z
Article
CAS
PubMed
Google Scholar
Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118. https://doi.org/10.1038/nrneurol.2012.263
Article
CAS
PubMed
PubMed Central
Google Scholar
McMillan CT, Lee EB, Jefferson-George K, Naj A, Van Deerlin VM, Trojanowski JQ et al (2018) Alzheimer's genetic risk is reduced in primary age-related tauopathy: a potential model of resistance? Ann Clin Transl Neurol 5:927–934. https://doi.org/10.1002/acn3.581
Article
CAS
PubMed
PubMed Central
Google Scholar
Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM et al (1991) The consortium to establish a registry for Alzheimer's disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41:479–486
Article
CAS
Google Scholar
Mishra A, Ferrari R, Heutink P, Hardy J, Pijnenburg Y, Posthuma D et al (2017) Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia. Brain 140:1437–1446. https://doi.org/10.1093/brain/awx066
Article
PubMed
Google Scholar
Miyazono M, Kitamoto T, Iwaki T, Tateishi J (1992) Colocalization of prion protein and beta protein in the same amyloid plaques in patients with Gerstmann-Sträussler syndrome. Acta Neuropathol 83:333–339
Article
CAS
Google Scholar
Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW et al (2012) National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol 123:1–11. https://doi.org/10.1007/s00401-011-0910-3
Article
CAS
PubMed
Google Scholar
Moore RA, Choi YP, Head MW, Ironside JW, Faris R, Ritchie DL et al (2016) Relative abundance of apoE and Aβ1-42 associated with abnormal prion protein differs between Creutzfeldt-Jakob disease subtypes. J Proteome Res 15:4518–4531
Article
CAS
Google Scholar
Moore RA, Faris R, Priola SA (2015) Proteomics applications in prion biology and structure. Expert Rev Proteomics 12:171–184. https://doi.org/10.1586/14789450.2015.1019481
Article
CAS
PubMed
Google Scholar
Moore RA, Sturdevant DE, Chesebro B, Priola SA (2014) Proteomics analysis of amyloid and nonamyloid prion disease phenotypes reveals both common and divergent mechanisms of neuropathogenesis. J Proteome Res 13:4620–4634. https://doi.org/10.1021/pr500329w
Article
CAS
PubMed
PubMed Central
Google Scholar
Morales R, Callegari K, Soto C (2015) Prion-like features of misfolded Aβ and tau aggregates. Virus Res 207:106–112. https://doi.org/10.1016/j.virusres.2014.12.031
Article
CAS
PubMed
Google Scholar
Morales R, Estrada LD, Diaz-Espinoza R, Morales-Scheihing D, Jara MC, Castilla J et al (2010) Molecular cross talk between misfolded proteins in animal models of Alzheimer's and prion diseases. J Neurosci 30:4528–4535. https://doi.org/10.1523/JNEUROSCI.5924-09.2010
Article
CAS
PubMed
PubMed Central
Google Scholar
Nakagawa Y, Kitamoto T, Furukawa H, Ogomori K, Tateishi J (1995) Allelic variation of apolipoprotein E in Japanese sporadic Creutzfeldt-Jakob disease patients. Neurosci Lett 187:209–211
Article
CAS
Google Scholar
Nakamura S, Ono F, Hamano M, Odagiri K, Kubo M, Komatsuzaki K et al (2000) Immunohistochemical detection of apolipoprotein E within prion-associated lesions in squirrel monkey brains. Acta Neuropathol 100:365–370
Article
CAS
Google Scholar
Parchi P, Cescatti M, Notari S, Schulz-Schaeffer WJ, Capellari S, Giese A et al (2010) Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease. Brain 133:3030–3042. https://doi.org/10.1093/brain/awq234
Article
PubMed
PubMed Central
Google Scholar
Parchi P, de Boni L, Saverioni D, Cohen ML, Ferrer I, Gambetti P et al (2012) Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathol 124:517–529. https://doi.org/10.1007/s00401-012-1002-8
Article
PubMed
PubMed Central
Google Scholar
Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O et al (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233
Article
CAS
Google Scholar
Parchi P, Notari S, Weber P, Schimmel H, Budka H, Ferrer I et al (2009) Inter-laboratory assessment of PrPSc typing in creutzfeldt-jakob disease: a Western blot study within the NeuroPrion consortium. Brain Pathol 19:384–391. https://doi.org/10.1111/j.1750-3639.2008.00187.x
Article
CAS
PubMed
Google Scholar
Parchi P, Strammiello R, Notari S, Giese A, Langeveld JP, Ladogana A et al (2009) Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 118:659–671. https://doi.org/10.1007/s00401-009-0585-1
Article
CAS
PubMed
PubMed Central
Google Scholar
Parchi P, Zou W, Wang W, Brown P, Capellari S, Ghetti B et al (2000) Genetic influence on the structural variations of the abnormal prion protein. Proc Natl Acad Sci U S A 97:10168–10172
Article
CAS
Google Scholar
Poleggi A, Bizzarro A, Acciarri A, Antuono P, Bagnoli S, Cellini E et al (2008) Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease. Eur J Neurol 15:173–178. https://doi.org/10.1111/j.1468-1331.2007.02021.x
Article
CAS
PubMed
Google Scholar
Rasmussen J, Krasemann S, Altmeppen H, Schwarz P, Schelle J, Aguzzi A et al (2018) Infectious prions do not induce Aβ deposition in an in vivo seeding model. Acta Neuropathol 135:965–967. https://doi.org/10.1007/s00401-018-1848-5
Article
CAS
PubMed
Google Scholar
Riemenschneider M, Klopp N, Xiang W, Wagenpfeil S, Vollmert C, Müller U et al (2004) Prion protein codon 129 polymorphism and risk of Alzheimer disease. Neurology 63:364–366
Article
CAS
Google Scholar
Ritchie DL, Adlard P, Peden AH, Lowrie S, Le Grice M, Burns K et al (2017) Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK. Acta Neuropathol 134:221–240. https://doi.org/10.1007/s00401-017-1703-0
Article
CAS
PubMed
PubMed Central
Google Scholar
Ritchie DL, Barria MA, Peden AH, Yull HM, Kirkpatrick J, Adlard P et al (2017) UK iatrogenic Creutzfeldt-Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches. Acta Neuropathol 133:579–595. https://doi.org/10.1007/s00401-016-1638-x
Article
CAS
PubMed
Google Scholar
Robinson JL, Lee EB, Xie SX, Rennert L, Suh E, Bredenberg C et al (2018) Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 141:2181–2193. https://doi.org/10.1093/brain/awy146
Article
PubMed
Google Scholar
Ruiz-Riquelme A, Lau HHC, Stuart E, Goczi AN, Wang Z, Schmitt-Ulms G et al (2018) Prion-like propagation of β-amyloid aggregates in the absence of APP overexpression. Acta Neuropathol Commun 6:26. https://doi.org/10.1186/s40478-018-0529-x
Article
CAS
PubMed
PubMed Central
Google Scholar
Salazar SV, Strittmatter SM (2016) Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease. Biochem Biophys Res Commun 483:1143–1147. https://doi.org/10.1016/j.bbrc.2016.09.062
Article
CAS
PubMed
PubMed Central
Google Scholar
Salvatore M, Seeber AC, Nacmias B, Petraroli R, D'Alessandro M, Sorbi S et al (1995) Apolipoprotein E in sporadic and familial Creutzfeldt-Jakob disease. Neurosci Lett 199:95–98
Article
CAS
Google Scholar
Sarell CJ, Quarterman E, Yip DC, Terry C, Nicoll AJ, Wadsworth JDF et al (2017) Soluble Aβ aggregates can inhibit prion propagation. Open Biol 7. https://doi.org/10.1098/rsob.170158
Article
Google Scholar
Schwarze-Eicker K, Keyvani K, Görtz N, Westaway D, Sachser N, Paulus W (2005) Prion protein (PrPc) promotes beta-amyloid plaque formation. Neurobiol Aging 26:1177–1182
Article
CAS
Google Scholar
Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W et al (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549:523–527. https://doi.org/10.1038/nature24016
Article
CAS
PubMed
PubMed Central
Google Scholar
Stevens M, van Duijn CM, de Knijff P, van Broeckhoven C, Heutink P, Oostra BA et al (1997) Apolipoprotein E gene and sporadic frontal lobe dementia. Neurology 48:1526–1529
Article
CAS
Google Scholar
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS et al (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90:1977–1981
Article
CAS
Google Scholar
Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R et al (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274:2079–2082
Article
CAS
Google Scholar
Van Everbroeck B, Croes EA, Pals P, Dermaut B, Jansen G, van Duijn CM et al (2001) Influence of the prion protein and the apolipoprotein E genotype on the Creutzfeldt-Jakob disease phenotype. Neurosci Lett 313:69–72
Article
Google Scholar
Varges D, Jung K, Gawinecka J, Heinemann U, Schmitz M, von Ahsen N et al (2011) Amyloid-β 1-42 levels are modified by apolipoprotein E ε4 in Creutzfeldt-Jakob disease in a similar manner as in Alzheimer's disease. J Alzheimers Dis 23:717–726. https://doi.org/10.3233/JAD-2010-101527
Article
CAS
PubMed
Google Scholar
Walker LC (2018) Prion-like mechanisms in Alzheimer disease. Handb Clin Neurol 153:303–319. https://doi.org/10.1016/B978-0-444-63945-5.00016-7
Article
PubMed
PubMed Central
Google Scholar
Wei Y, Tang Y, He W, Qu Z, Zeng J, Qin C (2014) APOE gene polymorphisms and susceptibility to Creutzfeldt-Jakob disease. J Clin Neurosci 21:390–394. https://doi.org/10.1016/j.jocn.2013.07.019
Article
CAS
PubMed
Google Scholar
Yoshida H, Terada S, Ishizu H, Ikeda K, Hayabara T, Ikeda K et al (2010) An autopsy case of Creutzfeldt-Jakob disease with a V180I mutation of the PrP gene and Alzheimer-type pathology. Neuropathology 30:159–164. https://doi.org/10.1111/j.1440-1789.2009.01048.x
Article
PubMed
Google Scholar
Zhang W, Jiao B, Xiao T, Pan C, Liu X, Zhou L et al (2016) Mutational analysis of PRNP in Alzheimer's disease and frontotemporal dementia in China. Sci Rep 6:38435. https://doi.org/10.1038/srep38435
Article
CAS
PubMed
PubMed Central
Google Scholar