The 2,6‐Disubstituted Naphthalene Derivative FDDNP Labeling Reliably Predicts Congo Red Birefringence of Protein Deposits in Brain Sections of Selected Human Neurodegenerative Diseases

Deposition of conformationally altered proteins prominently characterizes pathogenesis and pathomorphology of a number of neurodegenerative disorders. 2‐(1‐{6‐[(2‐[F‐18]fluoroethyl) (methyl)amino]‐2‐naphthyl} ethylidene) malononitrile ([F‐18]FDDNP), a hydrophobic, viscosity‐sensitive, solvent‐sensitive, fluorescent imaging probe has been used with positron emission tomography to visualize brain pathology in the living brain of Alzheimer disease (AD) patients. Its non‐radiofluorinated analog FDDNP was shown to label senile plaques and neurofibrillary tangles (NFTs) in brain tissue sections. This work aimed at evaluating FDDNP labeling of various protein deposits in fixed, paraffin‐embedded brain tissue sections of selected neurodegenerative disorders: AD, cerebral amyloid angiopathy (CAA), transmissible spongiform encephalopathies, progressive supranuclear palsy (PSP), Pick disease (PiD), Parkinson disease, dementia with Lewy bodies, multiple system atrophy (MSA). Cerebral hypertensive vascular hyalinosis (HVH) was used as negative control. Significant agreement between amyloid histochemical properties and FDDNP labeling of the deposits was established. FDDNP labeling showed high positive predictive value for birefringence in senile plaques and NFTs in AD, prion plaques and amyloid deposits in CAA. No FDDNP labeled structures were observed in HVH, PSP, PiD or MSA tissue sections. Our findings may be of significant value for the detection of neuropathological aggregates with [F‐18]FDDNP in some of these disorders in the living brain of human subjects.

[1]  W. Schlote,et al.  Tissue Handling in Suspected Creutzfeldt‐Jakob Disease (CJD) and Other Human Spongiform Encephalopathies (Prion Diseases) , 1995, Brain pathology.

[2]  R A Crowther,et al.  alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Christopher J. Johnson,et al.  Labeling of the scrapie-associated prion protein in vitro and in vivo , 2004, Neuroscience Letters.

[4]  J. Barrio,et al.  1,1-Dicyano-2-[6-(dimethylamino)naphthalen-2-yl]propene (DDNP): A Solvent Polarity and Viscosity Sensitive Fluorophore for Fluorescence Microscopy⊥ , 1996 .

[5]  J. Price,et al.  Cerebral amyloid deposition and diffuse plaques in ``normal'' aging , 1996, Neurology.

[6]  G. Small,et al.  Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. , 2002, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[7]  K. Hasegawa,et al.  Argyrophilic glial intracytoplasmic inclusions in multiple system atrophy: immunocytochemical and ultrastructural study , 2004, Acta Neuropathologica.

[8]  R. Crowther,et al.  α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies , 1998 .

[9]  L. Serpell,et al.  Molecular structure of a fibrillar Alzheimer's A beta fragment. , 2000, Biochemistry.

[10]  J. Barrio,et al.  Molecular-Imaging Probe 2-(1-{6-[(2-Fluoroethyl)(Methyl) Amino]-2-Naphthyl}Ethylidene) Malononitrile Labels Prion Plaques In Vitro , 2003, The Journal of Neuroscience.

[11]  J. Buxbaum.  The amyloidoses. , 1996, The Mount Sinai journal of medicine, New York.

[12]  S. Kato,et al.  Presence of two different fibril subtypes in the Pick body: an immunoelectron microscopic study , 2004, Acta Neuropathologica.

[13]  Sung-Cheng Huang,et al.  2-Dialkylamino-6-acylmalononitrile substituted naphthalenes (DDNP analogs): novel diagnostic and therapeutic tools in Alzheimer's disease. , 2003, Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging.

[14]  H. Puchtler,et al.  A review of light, polarization and fluorescence microscopic methods for amyloid. , 1985, Applied pathology.

[15]  K. Jellinger,et al.  Ageing and Dementia , 1998, Journal of Neural Transmission. Supplementa.

[16]  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.

[17]  P. Hof,et al.  Clinical validity of A beta-protein deposition staging in brain aging and Alzheimer disease. , 2001, Journal of neuropathology and experimental neurology.

[18]  J. Trojanowski,et al.  Synucleinopathies: a pathological and molecular review , 2001, Clinical Neuroscience Research.

[19]  Bart Kahr,et al.  Imaging linear birefringence and dichroism in cerebral amyloid pathologies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  F. Cohen,et al.  Evidence for assembly of prions with left-handed beta-helices into trimers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Yuji Sato,et al.  Congophilia in cerebral amyloidosis is modified by inactivation procedures on slow transmissible pathogens , 1986, Brain Research.

[22]  B. Shastry.  Neurodegenerative disorders of protein aggregation , 2003, Neurochemistry International.

[23]  Agneta Nordberg,et al.  PET imaging of amyloid in Alzheimer's disease , 2004, The Lancet Neurology.

[24]  Fred E. Cohen,et al.  Evidence for assembly of prions with left-handed β-helices into trimers , 2004 .

[25]  J. Kelly,et al.  Alternative conformations of amyloidogenic proteins govern their behavior. , 1996, Current opinion in structural biology.

[26]  J. Wall,et al.  Structural analysis of Pick's disease-derived and in vitro-assembled tau filaments. , 2001, The American journal of pathology.

[27]  D. Ron,et al.  Conformational disease , 2000, Nature Cell Biology.

[28]  M. Elghetany,et al.  The congo red stain revisited. , 1989, Annals of clinical and laboratory science.

[29]  E. Žerovnik,et al.  Amyloid-fibril formation. Proposed mechanisms and relevance to conformational disease. , 2002, European journal of biochemistry.

[30]  J. Trojanowski,et al.  New insights into genetic and molecular mechanisms of brain degeneration in tauopathies , 2000, Journal of Chemical Neuroanatomy.

[31]  K. McGraw,et al.  Forming inferences about some intraclass correlation coefficients. , 1996 .

[32]  S. Prusiner,et al.  Prion protein preamyloid and amyloid deposits in Gerstmann-Sträussler-Scheinker disease, Indiana kindred , 1992, Neurobiology of Aging.

[33]  William E. Klunk,et al.  The Binding of 2-(4′-Methylaminophenyl)Benzothiazole to Postmortem Brain Homogenates Is Dominated by the Amyloid Component , 2003, The Journal of Neuroscience.

[34]  J. Trojanowski,et al.  The fluorescent Congo red derivative, (trans, trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB), labels diverse beta-pleated sheet structures in postmortem human neurodegenerative disease brains. , 2001, The American journal of pathology.

[35]  J. Price,et al.  Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. , 1998, Archives of neurology.

[36]  Ž. Eva.  Amyloid-fibril formation: Proposed mechanisms and relevance to conformational disease , 2002 .

[37]  L. Serpell,et al.  Molecular Structure of a Fibrillar Alzheimer's Aβ Fragment† , 2000 .

[38]  A. Delacourte,et al.  Comparative Biochemistry of Tau in Progressive Supranuclear Palsy, Corticobasal Degeneration, FTDP‐17 and Pick's Disease , 1999, Brain pathology.

[39]  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.

[40]  M. Staufenbiel,et al.  A novel imaging probe for in vivo detection of neuritic and diffuse amyloid plaques in the brain , 2007, Journal of Molecular Neuroscience.

[41]  Christopher M Dobson,et al.  Principles of protein folding, misfolding and aggregation. , 2004, Seminars in cell & developmental biology.