Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline

Objective: To use functional MRI (fMRI) to investigate whether hippocampal activation during a memory task can predict cognitive decline in individuals with mild cognitive impairment (MCI). Methods: 25 older individuals with MCI performed a visual scene encoding task during fMRI scanning, and were followed clinically for at least 4 years after scanning. A hypothesis driven analysis of fMRI data was performed. First, fMRI data were analysed at the group level to identify the regions of the hippocampal formation that were engaged by this memory task. Parameter estimates of each subject’s memory related hippocampal activation (% signal change) were extracted and were analysed with a linear regression model to determine whether hippocampal activation predicted the degree or rate of cognitive decline, as measured by change in Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Results: Over 5.9 (1.2) years of follow-up after scanning, subjects varied widely in degree and rate of cognitive decline (change in CDR-SB ranged from 0 to 6, and the rate ranged from 0 to 1 CDR-SB unit/year). Greater hippocampal activation predicted greater degree and rate of subsequent cognitive decline (p<0.05). This finding was present even after controlling for baseline degree of impairment (CDR-SB), age, education and hippocampal volume, as well as gender and apolipoprotein E status. In addition, an exploratory whole brain analysis produced convergent results, demonstrating that the hippocampal formation was the only brain region where activation predicted cognitive decline. Conclusions: In individuals with MCI, greater memory task related hippocampal activation is predictive of a greater degree and rate of cognitive decline subsequent to scanning. fMRI may provide a physiological imaging biomarker useful for identifying the subgroup of MCI individuals at highest risk of cognitive decline for potential inclusion in disease modifying clinical trials.

[1]  B R Rosen,et al.  Encoding novel face‐name associations: A functional MRI study , 2001, Human brain mapping.

[2]  J. Wade,et al.  The clinical diagnosis of Alzheimer's disease. , 1987, Archives of neurology.

[3]  Robert C. Welsh,et al.  Aging and the Neural Correlates of Successful Picture Encoding: Frontal Activations Compensate for Decreased Medial-Temporal Activity , 2005, Journal of Cognitive Neuroscience.

[4]  J. Schneider,et al.  Neuropathology of older persons without cognitive impairment from two community-based studies , 2006, Neurology.

[5]  Cees Jonker,et al.  Medial temporal lobe atrophy and memory dysfunction as predictors for dementia in subjects with mild cognitive impairment , 1999, Journal of Neurology.

[6]  R. Faber,et al.  Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. , 1999, Neurology.

[7]  M. Albert,et al.  Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD , 2005, Neurology.

[8]  Vince D. Calhoun,et al.  Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer's Disease: An Independent Component Analysis , 2006, The Journal of Neuroscience.

[9]  M. Albert,et al.  Neuropsychological measures in normal individuals that predict subsequent cognitive decline. , 2007, Archives of neurology.

[10]  C. P. Hughes,et al.  A New Clinical Scale for the Staging of Dementia , 1982, British Journal of Psychiatry.

[11]  Brian J Bacskai,et al.  Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques. , 2004, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[12]  Jean-Francois Mangin,et al.  What is the best similarity measure for motion correction in fMRI time series? , 2002, IEEE Transactions on Medical Imaging.

[13]  C. Jack,et al.  Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia , 2002, Neurology.

[14]  B. Dickerson,et al.  MRI of human entorhinal cortex: a reliable protocol for volumetric measurement , 2001, Neurobiology of Aging.

[15]  C. Jack,et al.  Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment , 1999, Neurology.

[16]  D. Zaitchik,et al.  Psychiatric Symptomatology and Prodromal Alzheimer's Disease , 2003, Alzheimer disease and associated disorders.

[17]  D. Zaitchik,et al.  Predicting conversion to Alzheimer disease using standardized clinical information. , 2000, Archives of neurology.

[18]  D. A. Bennett,et al.  Memory complaints are related to Alzheimer disease pathology in older persons , 2006, Neurology.

[19]  Anders M. Dale,et al.  Cortical Surface-Based Analysis I. Segmentation and Surface Reconstruction , 1999, NeuroImage.

[20]  J Philip Miller,et al.  Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI , 2006, Neurology.

[21]  F. Schmitt,et al.  Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment , 2006, Neurobiology of Aging.

[22]  W R Markesbery,et al.  Risk factors for transitions from normal to mild cognitive impairment and dementia , 2006, Neurology.

[23]  A. Dale,et al.  Cortical Surface-Based Analysis II: Inflation, Flattening, and a Surface-Based Coordinate System , 1999, NeuroImage.

[24]  J. R. Baker,et al.  The hippocampal formation participates in novel picture encoding: evidence from functional magnetic resonance imaging. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Roger Kurlan,et al.  A focus on the synapse for neuroprotection in Alzheimer disease and other dementias , 2004, Neurology.

[26]  P. Cohen,et al.  Pharmacodynamic Considerations with Recombinant Human Insulin-Like Growth Factor-I in Children , 2005, Hormone Research in Paediatrics.

[27]  M. Albert,et al.  Preclinical prediction of AD using neuropsychological tests , 2001, Journal of the International Neuropsychological Society.

[28]  R. Killiany,et al.  Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease , 2000, Annals of neurology.

[29]  L. Freire,et al.  Motion Correction Algorithms May Create Spurious Brain Activations in the Absence of Subject Motion , 2001, NeuroImage.

[30]  M. Albert,et al.  Medial temporal lobe function and structure in mild cognitive impairment , 2004, Annals of neurology.

[31]  M. Albert,et al.  fMRI studies of associative encoding in young and elderly controls and mild Alzheimer’s disease , 2003, Journal of neurology, neurosurgery, and psychiatry.

[32]  D. Bennett,et al.  MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer’s disease☆ ☆ This research was supported by grants P01 AG09466 and P30 AG10161 from the National Institute on Aging, National Institutes of Health. , 2001, Neurobiology of Aging.

[33]  Edward A. Stern,et al.  Cortical Synaptic Integration In Vivo Is Disrupted by Amyloid-β Plaques , 2004, The Journal of Neuroscience.

[34]  D. Harvey,et al.  Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia , 2004, Neurology.

[35]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[36]  Deborah Blacker,et al.  Clinical prediction of Alzheimer disease dementia across the spectrum of mild cognitive impairment. , 2007, Archives of general psychiatry.