Ingenium 2021
Association between functional dedifferentiation and amyloid in preclinical Alzheimer’s Disease *Elizabeth J. Mountza, *Jinghang Lia, Akiko Mizuno, PhDb, Ashti M Shah, BSc, Andrea Weinstein, PhDb, Ann D. Cohen, PhDb, William E. Klunk, PhDb, d, Beth E. Snitz, PhDb, d, Howard J. Aizenstein, MD/PhDa, b, Helmet T. Karim, PhDb Department of Bioengineering, bDepartment of Psychiatry, Physician Scientist Training Program, University of Pittsburgh School of Medicine, dDepartment of Neurology * These authors contributed equally to this work. a c
Jinghang Li
Jinghang is a senior Biomedical Engineering student from Wenzhou, China. He has been working in the Geriatric psychiatry neuroimaging lab since May 2020. After graduation he plans on pursuing his PhD in Biomedical Engineering applying deep learning on imaging diagnostics. Elizabeth Mountz is a Junior studying Bioengineering at the University of Pittsburgh Swanson School of Engineering. She hopes to continue her research efforts in Graduate School.
Elizabeth J. Mountz
Howard J. Aizenstein, M.D., Ph.D.
Dr. Aizenstein is an expert on the cognitive and affective neuroscience of aging and geriatric brain disorders. He is trained as a geriatric psychiatrist and also a computer scientist. His research program is recognized for expertise in MRI analyses methods, as well as their use for clinical research in aging.
Significance Statement
Preclinical Alzheimer’s disease (AD) is a stage of AD defined by the presence of brain amyloid without overt cognitive impairment, occurring up to two decades prior to diagnosis. Amyloid may deposit asymmetrically, which has been shown to affect neural functional asymmetry in AD but not during the preclinical period. We show that altered functional asymmetry in the hippocampus may appear as early as the preclinical stages of AD and is associated with amyloid deposition.
CATEGORY: Experimental Research
Keywords: preclinical Alzheimer’s Disease, dedifferentiation, amyloid, memory encoding
Abstract
Preclinical Alzheimer’s disease (AD) is characterized by significant brain amyloid-β (Aβ) pathology without overt cognitive impairment. Aβ has been shown to deposit asymmetrically and has been shown to be associated with asymmetric brain glucose metabolism. In clinical AD, Aβ burden may exceed the compensatory reserve threshold, leading to greater neural functional asymmetry in AD individuals compared to elderly controls, where asymmetry is associated with cognitive function. To better understand AD progression, we investigated the association between markers of asymmetry, AD pathology, and cognitive function in cognitively normal older adults. Using fMRI during a memory encoding task, we calculated functional asymmetry and spread of activation in the hippocampus and dorsolateral prefrontal cortex, which are part of the core and extended memory network. Using positron emission tomography (PET), we measured brain Aβ and global glucose metabolism. We also collected data on APOE allele status and cognitive function. We conducted multivariate linear regression with measures of dedifferentiation (i.e., asymmetry index and spread of activation) as the outcome and markers of AD as independent variables. We additionally investigated their associations with domains of cognitive function. We found that greater global Aβ deposition was associated with greater hippocampal functional asymmetry and lower left hippocampal activation spread during a memory encoding task. Functional asymmetry and spread were not associated with cognitive function. Similar to studies in AD, we found that functional asymmetry was associated with greater Aβ in cognitively normal older individuals. This may hint at the early neurodegeneration in preclinical AD.
1. Introduction
Alzheimer’s disease (AD) is a process of progressive neurodegeneration which leads to severe cognitive dysfunction, including impairments in memory loss and executive control. AD is associated with a buildup of Amyloid-β (Aß) and neurofibrillary tangles in the brain. These cytotoxic proteins especially affect areas associated with memory, such as the hippocampus and dorsolateral prefrontal cortex (DLPFC) [1]. Greater Aß deposition, as measured by positron emission tomography (PET), is associated with functional changes in the brain including hippocampal atrophy, low cerebral glucose metabolism [2] and functional changes in neural activation as measured by functional magnetic resonance imaging (fMRI) [3]. Aß deposition is gradual with a preclinical stage where significant Aß deposition can be detected but no cognitive dysfunction is observed [4]. Aß deposition is often asymmetric, burdening one hemisphere more than the other [5]. One hypothesis for this lack of cognitive dysfunction with significant Aß pathology during the preclinical stage, is that compensatory neural recruitment can help delay cognitive dysfunction. In healthy individuals, neural activation is often lateralized and localized during tasks such as memory encoding due to the highly specialized roles of 55
