title: Cortical pyroglutamate amyloid-β levels and cognitive decline in Alzheimer's disease.
abstract: Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD). The relative concentrations of full-length Aβ and truncated, pyroglutamate-modified Aβ (NpE3) forms, and their correlations to cognitive dysfunction in AD, are unknown. We quantified AβNpE3-42, AβNpE3-40, Aβ1-42, and Aβ1-40 concentrations in soluble (nonfibrillar) and insoluble (fibrillar) pools in PCC from subjects with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment, or mild-moderate AD. In clinical AD, increased PCC concentrations of Aβ were observed for all Aβ forms in the insoluble pool but only for Aβ1-42 in the soluble pool. Lower Mini-Mental State Exam and episodic memory scores correlated most strongly with higher concentrations of soluble and insoluble Aβ1-42. Greater neuropathology severity by Consortium to Establish a Registry for Alzheimer's Disease and National Institute on Aging-Reagan pathologic criteria was associated with higher concentrations of all measured Aβ forms, except soluble AβNpE3-40. Low concentrations of soluble pyroglutamate Aβ across clinical groups likely reflect its rapid sequestration into plaques, thus, the conversion to fibrillar Aβ may be a therapeutic target.
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Violetta N
authors.initials: VN
authors.lastname: Pivtoraiko
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Abrahamson
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL.
authors.forename: Sue E
authors.initials: SE
authors.lastname: Leurgans
authors.affiliation: Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Steven T
authors.initials: ST
authors.lastname: DeKosky
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: ikonomovicmd@upmc.edu.
authors.forename: Milos D
authors.initials: MD
authors.lastname: Ikonomovic
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000523:psychology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003071:Cognition; D018450:Disease Progression; D005260:Female; D006179:Gyrus Cinguli / Q000378:metabolism*; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D010446:Peptide Fragments / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D011761:Pyrrolidonecarboxylic Acid
keywords: Alzheimer's disease; Amyloid-β; Episodic memory; MCI; Posterior cingulate cortex; Pyroglutamate-modified Aβ