Alzheimer's Disease Research
Reisa Sperling, M.D.
Brigham and Women's Hospital
Title: Cholinergic Vulnerability in Amyloid-Positive Elderly
Non-Technical Title: Susceptibility to drug-induced memory impairment in older subjects with amyloid
Duration: April 1, 2010 - September 30, 2013
Award Type: Standard
Award Amount: $399,143
This study will use a "scopolamine stress test" to test the hypothesis that older individuals harboring hidden amyloid pathology, as identified through brain imaging, are more vulnerable to the effects of the stress test on memory performance and functional MRI measures of memory network activity.
The brain changes in Alzheimer's disease likely begin years, perhaps even decades, prior to the time we make a diagnosis of dementia. We now have the ability, using neuroimaging, to detect some of these early brain changes, including one of the abnormal proteins that accumulate in the brain called "amyloid". Using these imaging techniques, we see that nearly one third of individuals over the age of 65 already show evidence of some amyloid in their brain. The problem is that we don't yet really know how amyloid causes the memory symptoms of Alzheimer's disease, and whether all older individuals who have amyloid in their brain will definitely develop Alzheimer's disease. These studies would take many years for the disease to develop, so we are using a "stress test" for the brain to try to see very early brain problems related to amyloid. This stress test involves using a very low dose of a drug that can cause short-term memory problems and is related to commonly available medicines which often cause confusion in older individuals. We will also examine brain function, using another neuroimaging technique, while the subjects are participate in tests of memory formation. We believe that amyloid build-up causes abnormalities in brain function, specifically in the parts of the brain that are important for memory, and that we will be able to see that older individuals with amyloid in their brain are more susceptible to the drug "stress test" and will show greater brain dysfunction during the memory tests. We will also investigate whether individuals with "cognitive reserve", that is people with especially "good brains" due to education and high IQ are protected against the effects of amyloid and the drug stress test. These studies are unique as they use cutting-edge neuroimaging to peer into the brains of living people. We hope that our findings will help us make the "link" between amyloid and the earliest memory problems in Alzheimer's disease, and perhaps one day, allow us to start clinical trials of promising medications to slow the progression of Alzheimer's disease, even before people have symptoms.
Vannini P, O'Brien J, O'Keefe K, Pihlajamaki MM, LaViolette P, Sperling RA. (2011) What goes down must come up: Role of the posteromedial cortices in encoding and retrieval. Cerebral Cortex, Jan; 1:22-34. Epub 2010 Apr 2.
Putcha D, O'Keefe K, LaViolette P, O'Brien J, Greve D, Locascio J, Atri A, Rentz DM, Sperling RA. (2011) Reliability of fMRI associative encoding memory paradigm in non-demented elderly adults. Human Brain Mapping, Dec; 32(12):2027-44. doi: 10.1002/hbm.21166. Epub 2011 Jan 21.
Becker JA, Hedden T, Carmasin J, Maye J, Rentz D, Putcha D, Fischl B, Greve D, Marshall GA, Salloway S, Marks D, Buckner RL, Sperling RA, Johnson KA. (2011) Amyloid-beta associated cortical thinning in clinically normal elderly. Annals of Neurology Jun; 69(6):1032-42. doi: 10.1002/ana.22333. Epub 2011 Mar 17.
Vannini P, Hedden T, Becker JA, Sullivan C, Putcha D, Rentz D, Johnson KA, Sperling RA. (2011) Age and amyloid-related alterations in default network habituation to stimulus repetition. Neurobiology of Aging, Jul; 33(7):1237-52. Epub 2011 Feb 18.
Atri A, O'Brien JL, Sreenivasan A, Rastegar S, Salisbury S, DeLuca AN, O'Keefe KM, LaViolette PS, Rentz DM, Locascio JJ, Sperling RA. (2011) Test-retest reliability of memory task fMRI in Alzheimer's disease clinical trials. Archives of Neurology, May; 68:5:599-606.
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan A, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, SternY, Yaffe K, Carillo MC, Thies W, Morrison-Bogorad M, Wagster M, Phelps CH. (2011) Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer Association Workgroup. Alzheimer's & Dementia, May; 7(3):280-92. Epub 2011 Apr 21.
Rentz DM, Amariglio RE, Becker JA, Frey M, Olson LE, Frishe K, Carmasin J, Maye JE, Johnson KA, Sperling RA. (2011) Face-Name Associative Memory Performance is Related to Amyloid Burden in Normal Elderly. Neuropsychologia, Jul; 49(9):2776-83. Epub 2011 Jun 12.
Sperling R, Jack CR, Aisen P. (2011) Testing the right target, the right drug, at the right stage: Secondary prevention trials in Alzheimer's disease. Science Translational Medicine, Nov 30;3(111):111cm33.
Amariglio R, Frishe K, Olson L, Wadsworth L, Lorius N, Sperling R, Rentz, D. (2012) Validation of the Face Name Memory Exam in cognitively normal older individuals. Journal of Clinical and Experimental Neuropsychology, Jul;34(6):580-7. Epub 2012 Mar 9.
Vannini P, Hedden T, Huijbers W, Ward A, Johnson KA, Sperling RA. (2013) The Ups and Downs of the Posteromedial Cortex: Age- and Amyloid-Related Functional Alterations of the Encoding/Retrieval Flip in Cognitively Normal Older Adults. Cerebral Cortex, Jun;23(6):1317-28. doi: 10.1093/cercor/bhs108. Epub 2012 May 14.
Dr. Sperling’s team is developing a "stress test" for the brain to try to detect very early brain problems related to amyloid. This stress test involves using a very low dose of a drug (called scopolamine) that can cause short-term memory problems and is related to commonly available medicines that often cause confusion in older individuals. The team will also examine brain function, using another neuroimaging technique, while the subjects are performing memory tests. They believe that amyloid build-up causes abnormalities in brain function, specifically in the parts of the brain that are important for memory. In addition, they think they will see that older individuals with amyloid in their brain are more susceptible to the drug "stress test" and will show greater brain dysfunction during the memory tests.
After over one year of preparatory work, the team has now begun the single-blind phase of testing to ensure that they have the correct dose of scopolamine. They have completed five subjects and have four more currently enrolled in the study. Dr. Sperling’s team has already detected evidence of subtle behavioral and functional imaging changes with low dose scopolamine.