Research towards tau imaging.

Tau-bearing neurofibrillary lesions present a promising biomarker for premortem diagnosis and staging of Alzheimer's disease and certain forms of frontotemporal lobar degeneration by whole brain imaging methods. Although brain penetrating compounds capable of binding tau aggregates with high affinity have been disclosed for this purpose, the major barrier to progress remains the need for tau lesion binding selectivity relative to amyloid-beta plaques and other deposits of proteins in cross-beta-sheet conformation. Here we discuss challenges faced in the development of tau lesion-selective imaging agents, and recent preclinical advances in pursuit of this goal.

[1]  A. Delacourte,et al.  Biochemistry of Tau in Alzheimer’s disease and related neurological disorders , 2008, Expert review of proteomics.

[2]  R. Riek,et al.  3D structure of Alzheimer's amyloid-β(1–42) fibrils , 2005 .

[3]  Seong Jin Cho,et al.  Voxel-based analysis of Alzheimer's disease PET imaging using a triplet of radiotracers: PIB, FDDNP, and FDG , 2010, NeuroImage.

[4]  V. Haroutunian,et al.  Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy , 2010, Neuron.

[5]  H. Braak,et al.  A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads , 2004, Acta Neuropathologica.

[6]  Kazuhiko Yanai,et al.  18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease. , 2011, Brain : a journal of neurology.

[7]  Vassar Ps,et al.  Fluorescent stains, with special reference to amyloid and connective tissues. , 1959 .

[8]  E. Mandelkow,et al.  Rapid assembly of Alzheimer-like paired helical filaments from microtubule-associated protein tau monitored by fluorescence in solution. , 1998, Biochemistry.

[9]  K. Jellinger,et al.  Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer's disease , 1989, Brain Research.

[10]  A. Donald,et al.  The binding of thioflavin-T to amyloid fibrils: localisation and implications. , 2005, Journal of structural biology.

[11]  Huan‐Xiang Zhou,et al.  Macromolecular crowding and confinement: biochemical, biophysical, and potential physiological consequences. , 2008, Annual review of biophysics.

[12]  P. Thompson,et al.  PET of brain amyloid and tau in mild cognitive impairment. , 2006, The New England journal of medicine.

[13]  Y. Duan,et al.  The binding of thioflavin T and its neutral analog BTA-1 to protofibrils of the Alzheimer's disease Abeta(16-22) peptide probed by molecular dynamics simulations. , 2008, Journal of molecular biology.

[14]  Cooper Jh Selective amyloid staining as a function of amyloid composition and structure. Histochemical analysis of the alkaline Congo red, standardized toluidine blue, and iodine methods. , 1974 .

[15]  S. Mazères,et al.  Thioflavin Derivatives as Markers for Amyloid‐β Fibrils: Insights into Structural Features Important for High‐Affinity Binding , 2008, ChemMedChem.

[16]  David Eisenberg,et al.  Recent atomic models of amyloid fibril structure. , 2006, Current opinion in structural biology.

[17]  P. Coleman,et al.  Neurons may live for decades with neurofibrillary tangles. , 1999, Journal of neuropathology and experimental neurology.

[18]  Robert A. Grothe,et al.  Structure of the cross-β spine of amyloid-like fibrils , 2005, Nature.

[19]  C. Jack,et al.  Voxel-based morphometry in autopsy proven PSP and CBD , 2008, Neurobiology of Aging.

[20]  H. Engler,et al.  Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. , 2006, Brain : a journal of neurology.

[21]  V. Adrian Parsegian,et al.  Van Der Waals Forces: A Handbook for Biologists, Chemists, Engineers, and Physicists , 2005 .

[22]  S. Leurgans,et al.  Tau Conformational Changes Correspond to Impairments of Episodic Memory in Mild Cognitive Impairment and Alzheimer's Disease , 2002, Experimental Neurology.

[23]  Mark Slifstein,et al.  Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography. , 2003, Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging.

[24]  A. Delacourte,et al.  Pathological Determinants of the Transition to Clinical Dementia in Alzheimer's Disease , 2002, Experimental aging research.

[25]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[26]  A. Gee,et al.  Evidence for the Presence of Three Distinct Binding Sites for the Thioflavin T Class of Alzheimer's Disease PET Imaging Agents on β-Amyloid Peptide Fibrils* , 2005, Journal of Biological Chemistry.

[27]  M. Kumbhakar,et al.  Ultrafast bond twisting dynamics in amyloid fibril sensor. , 2010, The journal of physical chemistry. B.

[28]  M. Viitanen,et al.  PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment , 2007, Neurology.

[29]  G. Small,et al.  Binding Characteristics of Radiofluorinated 6-Dialkylamino-2-Naphthylethylidene Derivatives as Positron Emission Tomography Imaging Probes for β-Amyloid Plaques in Alzheimer's Disease , 2001, The Journal of Neuroscience.

[30]  H. Braak,et al.  Frequency of Stages of Alzheimer-Related Lesions in Different Age Categories , 1997, Neurobiology of Aging.

[31]  H. Braak,et al.  Alzheimer’s disease: intraneuronal alterations precede insoluble amyloid-β formation , 2004, Neurobiology of Aging.

[32]  J. Kabat,et al.  Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament. , 1993, The EMBO journal.

[33]  Ronald Wetzel,et al.  Amyloid-like features of polyglutamine aggregates and their assembly kinetics. , 2002, Biochemistry.

[34]  V. Libri,et al.  Interaction of the amyloid imaging tracer FDDNP with hallmark Alzheimer’s disease pathologies , 2009, Journal of neurochemistry.

[35]  V. Libri,et al.  PIB is a non-specific imaging marker of amyloid-beta (Abeta) peptide-related cerebral amyloidosis. , 2007, Brain : a journal of neurology.

[36]  C. Jack,et al.  Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease , 2009, Brain : a journal of neurology.

[37]  Andrew Lockhart,et al.  In vitro high affinity α-synuclein binding sites for the amyloid imaging agent PIB are not matched by binding to Lewy bodies in postmortem human brain , 2008, Journal of neurochemistry.

[38]  I. Lascu,et al.  On the binding of Thioflavin-T to HET-s amyloid fibrils assembled at pH 2. , 2008, Journal of structural biology.

[39]  G. Glenner,et al.  β-PLEATED SHEET FIBRILS A COMPARISON OF NATIVE AMYLOID WITH SYNTHETIC PROTEIN FIBRILS , 1974, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[40]  J. Trojanowski,et al.  The Levels of Soluble versus Insoluble Brain Aβ Distinguish Alzheimer's Disease from Normal and Pathologic Aging , 1999, Experimental Neurology.

[41]  C. Duyckaerts,et al.  Prevalence, Incidence and Duration of Braak’s Stages in the General Population: Can We Know? , 1997, Neurobiology of Aging.

[42]  D. Dickson Neuropathology of Pick’s disease , 2001, Neurology.

[43]  Bruce L. Miller,et al.  Frontotemporal lobar degeneration , 2010, CNS drugs.

[44]  H. Cai,et al.  Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer's disease patients , 2004 .

[45]  C. Rowe,et al.  Imaging of amyloid β in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism , 2008, The Lancet Neurology.

[46]  Y. Duan,et al.  Dual binding modes of Congo red to amyloid protofibril surface observed in molecular dynamics simulations. , 2007, Journal of the American Chemical Society.

[47]  C. Rowe,et al.  Imaging β-amyloid burden in aging and dementia , 2007, Neurology.

[48]  I. Grundke‐Iqbal,et al.  Brain Levels of Microtubule‐Associated Protein τ Are Elevated in Alzheimer's Disease: A Radioimmuno‐Slot‐Blot Assay for Nanograms of the Protein , 1992, Journal of neurochemistry.

[49]  Maria Luisa Gorno-Tempini,et al.  Patterns of brain atrophy that differentiate corticobasal degeneration syndrome from progressive supranuclear palsy. , 2006, Archives of neurology.

[50]  M. Imaizumi,et al.  PET Measurement of the In Vivo Affinity of 11C-(R)-Rolipram and the Density of Its Target, Phosphodiesterase-4, in the Brains of Conscious and Anesthetized Rats , 2009, Journal of Nuclear Medicine.

[51]  J. Trojanowski,et al.  Regions with abundant neurofibrillary pathology in human brain exhibit a selective reduction in levels of binding-competent tau and accumulation of abnormal tau-isoforms (A68 proteins). , 1992, Laboratory investigation; a journal of technical methods and pathology.

[52]  H. P. Kao,et al.  Determinants of the translational mobility of a small solute in cell cytoplasm , 1993, The Journal of cell biology.

[53]  J. Morrison,et al.  Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease , 2003, Neurology.

[54]  P. Lantos,et al.  Office of Rare Diseases Neuropathologic Criteria for Corticobasal Degeneration , 2002, Journal of neuropathology and experimental neurology.

[55]  W. Klunk,et al.  Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. , 2001, Life sciences.

[56]  R. Tycko,et al.  Experimental constraints on quaternary structure in Alzheimer's beta-amyloid fibrils. , 2006, Biochemistry.

[57]  W. Klunk,et al.  X-34, A Fluorescent Derivative of Congo Red: A Novel Histochemical Stain for Alzheimer's Disease Pathology , 2000, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[58]  Michael Brady,et al.  A Biomathematical Modeling Approach to Central Nervous System Radioligand Discovery and Development , 2009, Journal of Nuclear Medicine.

[59]  M. Staufenbiel,et al.  Styrylbenzoxazole Derivatives for In Vivo Imaging of Amyloid Plaques in the Brain , 2004, The Journal of Neuroscience.

[60]  S. DeKosky,et al.  X-34 labeling of abnormal protein aggregates during the progression of Alzheimer's disease. , 2006, Methods in enzymology.

[61]  D. Dickson Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration , 1999, Journal of Neurology.

[62]  Tyler E. Benedum,et al.  Preclinical Properties of 18F-AV-45: A PET Agent for Aβ Plaques in the Brain , 2009, Journal of Nuclear Medicine.

[63]  Seong Jin Cho,et al.  Multitracer PET imaging of amyloid plaques and neurofibrillary tangles in Alzheimer's disease , 2008, NeuroImage.

[64]  J. Schneider,et al.  Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration , 2007, Acta Neuropathologica.

[65]  W. M. van der Flier,et al.  Detection of Alzheimer Pathology In Vivo Using Both 11C-PIB and 18F-FDDNP PET , 2009, Journal of Nuclear Medicine.

[66]  L. Thurfjell,et al.  Phase 1 Study of the Pittsburgh Compound B Derivative 18F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease , 2009, Journal of Nuclear Medicine.

[67]  Jans H. Alzate-Morales,et al.  Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[68]  J. Kuret,et al.  Imaging as a strategy for premortem diagnosis and staging of tauopathies. , 2010, Current Alzheimer Research.

[69]  M. Mintun,et al.  A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography , 1984, Annals of neurology.

[70]  P. Davies,et al.  A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[71]  Paul M Thompson,et al.  Current and future uses of neuroimaging for cognitively impaired patients , 2008, The Lancet Neurology.

[72]  R. Leapman,et al.  Seeded growth of β-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure , 2009, Proceedings of the National Academy of Sciences.

[73]  M. Pecul,et al.  Chiral bias of amyloid fibrils revealed by the twisted conformation of Thioflavin T: An induced circular dichroism/DFT study , 2005, FEBS letters.

[74]  Richard D. Leapman,et al.  Molecular structural basis for polymorphism in Alzheimer's β-amyloid fibrils , 2008, Proceedings of the National Academy of Sciences.

[75]  H. Gutiérrez‐de‐Terán,et al.  Crystal structure of thioflavin-T and its binding to amyloid fibrils: insights at the molecular level. , 2010, Chemical communications.

[76]  Bradley T. Hyman,et al.  Distribution of Alzheimer‐type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease , 1992, Neurology.

[77]  B. Vellas,et al.  Biomarkers in Alzheimer's Disease , 2009, Annals of the New York Academy of Sciences.

[78]  Michel Goedert,et al.  Tau protein and neurodegeneration. , 2004, Seminars in cell & developmental biology.

[79]  J. Morris,et al.  Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease , 1996, The Journal of Neuroscience.

[80]  H. Arai,et al.  Quinoline and Benzimidazole Derivatives: Candidate Probes for In Vivo Imaging of Tau Pathology in Alzheimer's Disease , 2005, The Journal of Neuroscience.

[81]  M. Biancalana,et al.  Binding modes of thioflavin-T to the single-layer beta-sheet of the peptide self-assembly mimics. , 2009, Journal of molecular biology.

[82]  W. Dzwolak,et al.  Chiral bifurcation in aggregating insulin: an induced circular dichroism study. , 2008, Journal of molecular biology.

[83]  M. Groenning,et al.  Binding mode of Thioflavin T and other molecular probes in the context of amyloid fibrils—current status , 2010, Journal of chemical biology.

[84]  David Eisenberg,et al.  Structural studies of amyloid , 2005 .