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NEUROLOGY 2007;69:1331-1341
© 2007 American Academy of Neurology

Relationship of fMRI activation to clinical trial memory measures in Alzheimer disease

E. L. Diamond, MD, MPhil, S. Miller, BA, B. C. Dickerson, MD, A. Atri, MD, PhD, K. DePeau, BA, E. Fenstermacher, BA, M. Pihlajamäki, MD, PhD, K. Celone, BA, S. Salisbury, BA, M. Gregas, PhD, D. Rentz, PsyD and R. A. Sperling, MD

From the Department of Neurology (E.L.D., B.C.D., A.A., K.D., M.P., S.S., D.R., R.A.S.), Brigham and Women’s Hospital, Boston; Departments of Neurology (B.C.D., A.A., R.A.S.) and Psychiatry (S.M., E.F., K.C.) and the Athinoula A. Martinos Center for Biomedical Imaging (E.L.D., S.M., B.C.D., K.D., E.F., R.A.S.), Massachusetts General Hospital and Harvard Medical School, Boston; Department of Biostatistics (M.G.), Harvard School of Public Health, Boston, MA; Department of Neuroscience and Neurology (M.P.), University of Kuopio, Finland; and Albert Einstein College of Medicine (E.L.D.), Bronx, NY.

Address correspondence and reprint requests to Dr. Reisa A. Sperling, Memory Disorders Unit, Brigham and Women’s Hospital, 221 Longwood Ave, Boston, MA 02115 reisa{at}rics.bwh.harvard.edu

Background: Functional MRI (fMRI) has shown promise as a tool to characterize altered brain function in Alzheimer disease (AD) and for use in proof of concept clinical trials. FMRI studies of subjects with AD have demonstrated altered hippocampal and neocortical activation while encoding novel stimuli compared to older controls. However, the relationship between fMRI activation and performance on standardized clinical trial memory measures has not been fully investigated.

Objective: To determine whether patterns of activation during an associative-memory fMRI paradigm correlate with performance on memory measures used in AD clinical trials.

Methods: Twenty-nine subjects with AD underwent neuropsychological testing, including the AD Assessment Scale (ADAS-Cog), and an associative-encoding fMRI paradigm. Scores were entered as regressors in SPM2 analyses of the differential fMRI activation to novel-vs-repeated (NvR) stimuli. To account for cerebral atrophy, native-space structure-function analyses were performed with subjects’ high-resolution structural images.

Results: Performance on the ADAS-Cog verbal memory component, and the ADAS-Cog total score, correlated with NvR activation in left superior temporal (p = 0.0003; r = –0.51) and left prefrontal (p = 0.00001; r = –0.63) cortices. In a subgroup with more extensive neuropsychological testing (n = 14), performance on the Free and Cued Selective Reminding Test was correlated with activation in these same regions. fMRI activation remained correlated with performance even when accounting for atrophy.

Conclusions: The relationship between functional MRI (fMRI) activation and standardized memory measures supports the potential use of fMRI to investigate regional mechanisms of treatment response in clinical trials of novel therapies for Alzheimer disease.

GLOSSARY: AD = Alzheimer disease; ADAS-Cog = AD Assessment Scale; EPI = echoplanar imaging sequence; FA = flip angle; FCSRT = Free and Cued Selective Reminding Test; FLAME = FMRIB’s Local Analysis of Mixed Effects; fMRI = Functional MRI; FOV = field of view; GLM = general linear model; HRF = hemodynamic response function; LFG = left fusiform gyrus; LPFC = left prefrontal cortex; LSTG = left superior temporal gyrus; MMSE = Mini-Mental State Examination; MTL = medial temporal lobe; NvR = novel-vs-repeated; ROI = region of interest; TE = echo time; TR = repetition time.

Supplemental data at www.neurology.org

Supported by NIA-PO1-AG04953; NIA-R01-AG027435; P50-AG00513421; NIH-T32 Pre-Doctoral Training Program in Aging Research; Eli Lilly; Forest Laboratories; Albert Einstein Medical Student Research Fellowship; AFAR Beeson Scholars in Aging Program; Academy of Finland.

Disclosures: Dr. Dickerson has received research support from Pfizer and Janssen. Dr. Atri received consultation fees and lecture honoraria from Forest Laboratories. He received lecture honoraria from Pfizer. Dr. Sperling has received research support from Eli Lilly, Glaxo Smith Kline, and Forest Laboratories. She has received support for clinical trials from Wyeth/Elan and Neurochem. She has received lecture honoraria from Janssen, Novartis, Forest Laboratories, and Pfizer.

Received October 18, 2006. Accepted in final form April 20, 2007.






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