OBJECTIVE: For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the "preclinical" (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD. METHODS: We investigated the relation between structural neuroimaging measures (whole-brain volume) and levels of CSF amyloid-beta (Abeta)(40), Abeta(42), tau, and phosphorylated tau(181) (ptau(181)), and plasma Abeta(40) and Abeta(42) in well-characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age-matched, cognitively normal control subjects (n = 69). RESULTS: Levels of CSF tau and ptau(181), but not Abeta(42), correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Abeta(42), but not tau or ptau(181), were positively correlated with whole-brain volume in nondemented control subjects. INTERPRETATION: Reduction in CSF Abeta(42), likely reflecting Abeta aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Abeta aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau(181)) are later events that correlate with further structural damage and occur with clinical onset and progression.
OBJECTIVE: For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the "preclinical" (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD. METHODS: We investigated the relation between structural neuroimaging measures (whole-brain volume) and levels of CSF amyloid-beta (Abeta)(40), Abeta(42), tau, and phosphorylated tau(181) (ptau(181)), and plasma Abeta(40) and Abeta(42) in well-characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age-matched, cognitively normal control subjects (n = 69). RESULTS: Levels of CSF tau and ptau(181), but not Abeta(42), correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Abeta(42), but not tau or ptau(181), were positively correlated with whole-brain volume in nondemented control subjects. INTERPRETATION: Reduction in CSF Abeta(42), likely reflecting Abeta aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Abeta aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau(181)) are later events that correlate with further structural damage and occur with clinical onset and progression.
Authors: Anne M Fagan; Mark A Mintun; Robert H Mach; Sang-Yoon Lee; Carmen S Dence; Aarti R Shah; Gina N LaRossa; Michael L Spinner; William E Klunk; Chester A Mathis; Steven T DeKosky; John C Morris; David M Holtzman Journal: Ann Neurol Date: 2006-03 Impact factor: 10.422
Authors: M J de Leon; S DeSanti; R Zinkowski; P D Mehta; D Pratico; S Segal; H Rusinek; J Li; W Tsui; L A Saint Louis; C M Clark; C Tarshish; Y Li; L Lair; E Javier; K Rich; P Lesbre; L Mosconi; B Reisberg; M Sadowski; J F DeBernadis; D J Kerkman; H Hampel; L-O Wahlund; P Davies Journal: Neurobiol Aging Date: 2005-08-26 Impact factor: 4.673
Authors: Oskar Hansson; Henrik Zetterberg; Peder Buchhave; Elisabet Londos; Kaj Blennow; Lennart Minthon Journal: Lancet Neurol Date: 2006-03 Impact factor: 44.182
Authors: G Li; I Sokal; J F Quinn; J B Leverenz; M Brodey; G D Schellenberg; J A Kaye; M A Raskind; J Zhang; E R Peskind; T J Montine Journal: Neurology Date: 2007-08-14 Impact factor: 9.910
Authors: Hilary A Archer; Paul Edison; David J Brooks; Jo Barnes; Chris Frost; Tom Yeatman; Nick C Fox; Martin N Rossor Journal: Ann Neurol Date: 2006-07 Impact factor: 10.422
Authors: Liana G Apostolova; Kristy S Hwang; John P Andrawis; Amity E Green; Sona Babakchanian; Jonathan H Morra; Jeffrey L Cummings; Arthur W Toga; John Q Trojanowski; Leslie M Shaw; Clifford R Jack; Ronald C Petersen; Paul S Aisen; William J Jagust; Robert A Koeppe; Chester A Mathis; Michael W Weiner; Paul M Thompson Journal: Neurobiol Aging Date: 2010-06-11 Impact factor: 4.673
Authors: Guy M McKhann; David S Knopman; Howard Chertkow; Bradley T Hyman; Clifford R Jack; Claudia H Kawas; William E Klunk; Walter J Koroshetz; Jennifer J Manly; Richard Mayeux; Richard C Mohs; John C Morris; Martin N Rossor; Philip Scheltens; Maria C Carrillo; Bill Thies; Sandra Weintraub; Creighton H Phelps Journal: Alzheimers Dement Date: 2011-04-21 Impact factor: 21.566
Authors: Clifford R Jack; Prashanthi Vemuri; Heather J Wiste; Stephen D Weigand; Timothy G Lesnick; Val Lowe; Kejal Kantarci; Matt A Bernstein; Matthew L Senjem; Jeffrey L Gunter; Bradley F Boeve; John Q Trojanowski; Leslie M Shaw; Paul S Aisen; Michael W Weiner; Ronald C Petersen; David S Knopman Journal: Arch Neurol Date: 2012-07
Authors: Soyon Hong; Omar Quintero-Monzon; Beth L Ostaszewski; Daniel R Podlisny; William T Cavanaugh; Ting Yang; David M Holtzman; John R Cirrito; Dennis J Selkoe Journal: J Neurosci Date: 2011-11-02 Impact factor: 6.167
Authors: Roy Yaari; Adam S Fleisher; Anna D Burke; Helle Brand; Jan Dougherty; James D Seward; Pierre N Tariot Journal: Prim Care Companion CNS Disord Date: 2011
Authors: Nigel J Cairns; Milos D Ikonomovic; Tammie Benzinger; Martha Storandt; Anne M Fagan; Aarti R Shah; Lisa Taylor Reinwald; Deborah Carter; Angela Felton; David M Holtzman; Mark A Mintun; William E Klunk; John C Morris Journal: Arch Neurol Date: 2009-12