Functional alterations contribute to memory deficits in aging and AD: an fMRI and PET study

1179 

Abstract Submission 

Xi Chen¹, Leah Varghese², Suzanne Baker³, William Jagust⁴

¹Stony Brook University, Stony Brook, NY, ²Stanford University School of Medicine, Palo Alto, CA, ³Lawrence Berkeley National Laboratory, Berkeley, CA, ⁴University of California, Berkeley, Berkeley, CA

Xi Chen  
Stony Brook University
Stony Brook, NY

Leah Varghese  
Stanford University School of Medicine
Palo Alto, CA

Suzanne Baker  
Lawrence Berkeley National Laboratory
Berkeley, CA

William Jagust  
University of California, Berkeley
Berkeley, CA

The anterior temporal (AT) and posterior medial (PM) networks, and hippocampus in the medial temporal lobe (MTL) are functionally responsible for object/item-based, scene/context-based, and association/integrative processing for episodic memory, respectively [1]. These systems are also vulnerable to aging and Alzheimer's disease (AD) [2,3]. AD pathology of beta-amyloid (Aβ) and tau begins to emerge in cognitively normal people before clinical symptoms [4,5], and it preferentially deposits first in AT, PM, and MTL in this pre-clinical, asymptomatic stage [2]. Given the functional specificity of these regions and their particular vulnerability to AD pathology, we hypothesize that age-related and pathology-related memory deficits may be explained by functional alterations in these regions. Here, we utilized multimodal neuroimaging, including task fMRI to assess functional activation during incidental memory encoding, and PET imaging to measure Aβ and tau burden in cognitively normal older individuals. We aimed to study the neural bases of memory deficits in normal aging and early AD.

Twenty-seven young (19-34 yrs) and 51 older (60-91 yrs) participants completed a memory task [6] where the incidental encoding of object, scene, and object-in-scene pair images was scanned during fMRI and a subsequent recognition test approximately 45 minutes later was performed outside the scanner (Fig 1A). Forty-one older participants also underwent PiB and FTP PET scans to measure their Aβ and tau burden. We examined age-related (young vs. older) and AD pathology related (Aβ- vs. Aβ+, continuous tau) effects for subsequent memory performance, indexed by accuracy and d', and brain activations. The fMRI analysis was focused on the composite regions of interest (ROIs) of AT and PM (Fig 1B), as well as the hippocampus, for the pair > object + scene contrast.

Behaviorally, older people had worse object and pair memory, primarily driven by an increased difficulty in distinguishing lures (Fig 1C). Older people in the pre-clinical stage of AD, evidenced by Aβ positivity and elevated temporal meta tau burden, exhibited even worse memory, with a greater difficulty in remembering the previously presented pictures, compared to those without AD pathology (Fig 1C). FMRI results show that all three ROIs had significant activations during the processing of pairs in contrast to object-alone and scene-alone materials (Fig 2A), where greater activation was predictive of better subsequent memory performance indexed by accuracy (Fig 1D). Older age was associated with reduced activation in AT (Fig 2A), which marginally mediated the age-related differences in subsequent memory accuracy (Fig 2C). In contrast, greater tau pathology was associated with increased activation in the parahippocampal gyrus (Fig 2B), which completely mediated the tau-related differences in subsequent memory d' (Fig 2D).

Older adults have worse memory, especially for complex object-in-scene pairs, primarily driven by greater false recognition of lures. AT, PM, and hippocampus are all significantly involved in processing object-in-scene pairs. The age-related functional reductions in AT regions contribute to worse task performance, especially the greater difficulty in rejecting lures. Additionally, AD pathology was associated with a further reduction in pair memory performance, most evident in failure to remember old pictures. Greater tau pathology was associated with increased activation that contributed significantly to worse subsequent memory. In conclusion, functional activation may play important roles through different mechanisms underlying memory deficits in normal aging and early AD: functional reduction in key task regions may contribute, to some extent, to worse memory task performance in aging, whereas tau-induced hyperactivation explains the disproportionately worse performance in pre-clinical AD.

Aging ¹

Activation (eg. BOLD task-fMRI) ²

Aging

Cognition

FUNCTIONAL MRI

Memory

NORMAL HUMAN

Positron Emission Tomography (PET)

Other - Alzheimer's disease