BACKGROUND: Previous cross-sectional fMRI studies in subjects with prodromal Alzheimer disease (AD) have reported variable results, ranging from hypoactivation, similar to patients with AD, to paradoxically increased activation or hyperactivation compared to cognitively normal older individuals. We have hypothesized that subjects in early phases of prodromal AD may experience a period of hippocampal hyperactivation, followed by loss of hippocampal activation as the disease progresses. METHODS: We studied 51 older individuals without dementia (Clinical Dementia Rating [CDR] at baseline of 0, n = 21, and 0.5, n = 30) with longitudinal clinical and neuropsychological assessments, as well as fMRI during a face-name associative memory paradigm. Whole brain and region-of-interest analyses were applied to the longitudinal fMRI data. RESULTS: Subjects classified as CDR 0 at baseline showed no difference in fMRI activity over 2 years, whereas those who were CDR 0.5 at baseline demonstrated a decrease in fMRI activity in the right hippocampus (p < 0.001). Dividing the subjects on the basis of their clinical and neuropsychological change over the 2 years, we found that subjects with more rapid decline demonstrated both the highest hippocampal activation at baseline, and the greatest loss of hippocampal activation. These findings remained significant after accounting for age, hippocampal volume, and APOE epsilon4 carrier status. CONCLUSIONS: Clinical decline is associated with loss of hippocampal activation in older subjects. Longitudinal fMRI provides a reliable indicator of brain activation over time, and may prove useful in identifying functional brain changes associated with cognitive decline on the trajectory toward clinical Alzheimer disease.
BACKGROUND: Previous cross-sectional fMRI studies in subjects with prodromal Alzheimer disease (AD) have reported variable results, ranging from hypoactivation, similar to patients with AD, to paradoxically increased activation or hyperactivation compared to cognitively normal older individuals. We have hypothesized that subjects in early phases of prodromal AD may experience a period of hippocampal hyperactivation, followed by loss of hippocampal activation as the disease progresses. METHODS: We studied 51 older individuals without dementia (Clinical Dementia Rating [CDR] at baseline of 0, n = 21, and 0.5, n = 30) with longitudinal clinical and neuropsychological assessments, as well as fMRI during a face-name associative memory paradigm. Whole brain and region-of-interest analyses were applied to the longitudinal fMRI data. RESULTS: Subjects classified as CDR 0 at baseline showed no difference in fMRI activity over 2 years, whereas those who were CDR 0.5 at baseline demonstrated a decrease in fMRI activity in the right hippocampus (p < 0.001). Dividing the subjects on the basis of their clinical and neuropsychological change over the 2 years, we found that subjects with more rapid decline demonstrated both the highest hippocampal activation at baseline, and the greatest loss of hippocampal activation. These findings remained significant after accounting for age, hippocampal volume, and APOE epsilon4 carrier status. CONCLUSIONS: Clinical decline is associated with loss of hippocampal activation in older subjects. Longitudinal fMRI provides a reliable indicator of brain activation over time, and may prove useful in identifying functional brain changes associated with cognitive decline on the trajectory toward clinical Alzheimer disease.
Authors: Reisa Sperling; Douglas Greve; Anders Dale; Ronald Killiany; Jennifer Holmes; H Diana Rosas; Andrew Cocchiarella; Paul Firth; Bruce Rosen; Stephen Lake; Nicholas Lange; Carol Routledge; Marilyn Albert Journal: Proc Natl Acad Sci U S A Date: 2001-12-26 Impact factor: 11.205
Authors: R A Sperling; J F Bates; E F Chua; A J Cocchiarella; D M Rentz; B R Rosen; D L Schacter; M S Albert Journal: J Neurol Neurosurg Psychiatry Date: 2003-01 Impact factor: 10.154
Authors: Bradford C Dickerson; David H Salat; Julianna F Bates; Monika Atiya; Ronald J Killiany; Douglas N Greve; Anders M Dale; Chantal E Stern; Deborah Blacker; Marilyn S Albert; Reisa A Sperling Journal: Ann Neurol Date: 2004-07 Impact factor: 10.422
Authors: S Y Bookheimer; M H Strojwas; M S Cohen; A M Saunders; M A Pericak-Vance; J C Mazziotta; G W Small Journal: N Engl J Med Date: 2000-08-17 Impact factor: 91.245
Authors: Michael Grundman; Ronald C Petersen; Steven H Ferris; Ronald G Thomas; Paul S Aisen; David A Bennett; Norman L Foster; Clifford R Jack; Douglas R Galasko; Rachelle Doody; Jeffrey Kaye; Mary Sano; Richard Mohs; Serge Gauthier; Hyun T Kim; Shelia Jin; Arlan N Schultz; Kimberly Schafer; Ruth Mulnard; Christopher H van Dyck; Jacobo Mintzer; Edward Y Zamrini; Deborah Cahn-Weiner; Leon J Thal Journal: Arch Neurol Date: 2004-01
Authors: M M Machulda; H A Ward; B Borowski; J L Gunter; R H Cha; P C O'Brien; R C Petersen; B F Boeve; D Knopman; D F Tang-Wai; R J Ivnik; G E Smith; E G Tangalos; C R Jack Journal: Neurology Date: 2003-08-26 Impact factor: 9.910
Authors: J Carson Smith; Kristy A Nielson; John L Woodard; Michael Seidenberg; Sally Durgerian; Piero Antuono; Alissa M Butts; Nathan C Hantke; Melissa A Lancaster; Stephen M Rao Journal: Neuroimage Date: 2010-08-05 Impact factor: 6.556
Authors: Marc Aurel Busche; Xiaowei Chen; Horst A Henning; Julia Reichwald; Matthias Staufenbiel; Bert Sakmann; Arthur Konnerth Journal: Proc Natl Acad Sci U S A Date: 2012-05-16 Impact factor: 11.205
Authors: Kathryn V Papp; Rebecca E Amariglio; Maria Dekhtyar; Kamolika Roy; Sarah Wigman; Rose Bamfo; Julia Sherman; Reisa A Sperling; Dorene M Rentz Journal: Clin Neuropsychol Date: 2014-05-12 Impact factor: 3.535
Authors: Nathaniel S Woodling; Damien Colas; Qian Wang; Paras Minhas; Maharshi Panchal; Xibin Liang; Siddhita D Mhatre; Holden Brown; Novie Ko; Irene Zagol-Ikapitte; Marieke van der Hart; Taline V Khroyan; Bayarsaikhan Chuluun; Prachi G Priyam; Ginger L Milne; Arash Rassoulpour; Olivier Boutaud; Amy B Manning-Boğ; H Craig Heller; Katrin I Andreasson Journal: Brain Date: 2016-05-13 Impact factor: 13.501