Project: Brain Amyloid and Cognition in Normal Elderly

P.Is.: William E. Klunk, M.D., Ph.D, Howard J. Aizenstein, M.D., Ph.D,

The overarching goal of this project is to further the understanding of the occurrence of asymptomatic amyloid-beta (Aβ) deposition and its progression to clinical cognitive impairment. The project has been ongoing for 11 years and is expected to continue for another five year cycle beginning in 4Q 2020. In the first eight years of this project, [11C]PiB PET scans, MR images, and cognitive data were collected in 75 cognitively normal elderly to determine whether or not the variability in cognition in this cohort was explained by baseline Aload and found that it was not. As the cohort continues to mature, a growing number of have converted to mild cognitive impairment (MCI) and cases of incident Aβ positivity have been identified. Continued follow-up of this cohort will help to establish the incidence of asymptomatic β-amyloidosis, understand the relationship between the earliest phases of Aβ deposition in incident Aβ positive subjects, hippocampal fMRI activation, and the temporal relationship between asymptomatic β-amyloidosis and the emergence of objective cognitive abnormalities in subjects converting to MCI. Since its inception in 2005, over 90 peer-reviewed scientific papers have been published relating to this project:

Selected Recent Publications:

Sullivan KJ, Liu A, Chang CH, Cohen AD, Lopresti BJ, Minhas DS, Laymon CM, Klunk WE, Aizenstein H, Nadkarni NK, Loewenstein D, Kamboh MI, Ganguli M, Snitz BE (2020). Alzheimer’s disease pathology in a community based-sample of older adults without dementia. Brain Imaging Behav. Aug 3. doi: 10.1007/s11682-020-00334-2. Online ahead of print

Lopresti BJ, Campbell EM, Yu Z, Anderson SJ, Cohen AD, Minhas DS, Snitz BE, Royse SK, Becker CR, Aizenstein HJ, Mathis CA, Lopez OL, Klunk WE, Tudorascu DL (2020). Influence of apolipoprotein-E genotype on brain amyloid load and longitudinal trajectories. Neurobiol. of Aging 94: 111-120.

Karim HT, Tudorascu DL, Cohen A, Price JC, Lopresti B, Mathis C, Klunk W, Snitz BE, Aizenstein HJ (2019). Relationships between executive control circuit activity, amyloid burden, and education in cognitively healthy older adults. Am. J. Geriatr. Psychiatry 27:1360-1371.

Wu M, Thurston RC, Tudorascu DL, Karim HT, Mathis CA, Lopresti BJ, Kamboh MI, Cohen AD, Snitz BE, Klunk WE, Aizenstein HJ (2019). Amyloid deposition is associated with different patterns of hippocampal connectivity in men versus women. Neurobiol. Aging 76:141-150.

Tudorascu DL, Anderson SJ, Minhas DS, Yu Z, Comer D, Lao P, Hartley S, Laymon CM, Snitz BE, Lopresti BJ, Johnson S, Price JC, Mathis CA, Aizenstein HJ, Klunk WE, Handen BL, Christian BT, Cohen AD (2019). Comparison of longitudinal Aβ in nondemented elderly and Down syndrome. Neurobiol. Aging 73:171-176.

Key Publications

Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, Bi W, Cohen AD, Lopresti BJ, DeKosky ST, Halligan EM, Klunk WE (2008). Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch. Neurol. 65:1509-1517.

Wolk DA, Price JC, Saxton JA, Snitz BE, James JA, Lopez OL, Aizenstein HJ, Cohen AD, Weissfeld LA, Mathis CA, Klunk WE, DeKosky ST (2009). Amyloid imaging in mild cognitive impairment subtypes. Ann. Neurol. 65:557-568.

Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Paljug WR, Debnath MK, Hope CE, Isanski BA, Hamilton RL, DeKosky ST (2008). Post-mortem correlates of in vivo PIB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain 131:1630-45.

From Aizenstein et al., 2008. Mean distribution volume ratio (DVR) images for 29 amyloid-negative clinically unimpaired participants (left), 9 amyloid-positive clinically unimpaired participants (center), and 9 patients with Alzheimer disease (AD) (right)

From Wolk et al, 2009: A) Mean distribution volume ratio (DVR) images of amyloid-negative control subjects, amyloid-negative patients with amnestic mild cognitive impairment (a-MCI), representative group of patients with Alzheimer’s disease (AD), amyloid-positive patients with a-MCI, and amyloid-positive patients with nonamnestic MCI (na-MCI). B) Individual DVR images of the three amyloid-positive patients with na-MCI.