Neuroimaging Predictors of Alzheimer's Disease and Cognitive Decline

National Institute On Aging

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Abstract

Through our research program on early markers of Alzheimers disease (AD), we continue to perform serial magnetic resonance imaging (MRI), including measures of vascular changes, positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiologic basis of individual differences in memory change over time, as well as predictors of cognitive impairment and resilience. These evaluations allow us to examine changes in brain structure and function which may be early preclinical predictors of cognitive change, impairment, including AD, and resilience or maintenance of cognitive health. Neuroimaging studies are also useful in investigating modifiers of cognitive and brain changes, including sex differences in cognitive and brain aging, genetic, metabolic, and inflammatory risk factors. Early detection of accelerated brain changes during the preclinical or asymptomatic stages of disease will be critical in identifying individuals likely to benefit from interventions if a successful treatment for prevention or delaying onset of AD is available. Longitudinal neuroimaging evaluations of BLSA participants began in 1994 with approximately 160 individuals aged 55-85 at enrollment. In 2009, we expanded MRI assessments to more than 1000 individuals (with greater than 60% receiving 2 or more scans) and cognitive assessments. At present, MRI scans are conducted in conjunction with BLSA visits which vary by age: annually for individuals 80 and older, every two years for individuals 60-79, and every four years for those less than 60. For a subsample aged 55 and older, we performed PET scans using 11-C-Pittsburgh Compound B (PiB) to measure in vivo amyloid deposition in approximately 230 individuals to date, with close to 70% receiving two or more PiB scans. PET measurements of cerebral blood flow were also done in a subset of participants through 2015. In 2016, we initiated Tau PET (AV-1451) studies of BLSA participants receiving PET amyloid scans (separate annual report), with more than 100 individuals receiving Tau PET to date. MRI and PET studies of BLSA participants were suspended in March 2020 due to the COVID19 pandemic. We reinitiated our PET amyloid and tau studies in July 2021, albeit at a much reduced level due to the decreased BLSA participant flow and the need to restrict studies to local participants. Our progress over the last year has focused on analyses of existing data, and methods development of new approaches to analysis of longitudinal neuroimaging data. In addition, we took advantage of newly available Simoa assays to investigate AD biomarkers and modifiers. In collaboration with Drs. Moghekar and Walker, we have completed Quanterix Neuro4plex plasma assays for ABeta40, ABeta42, Neurofilament Light and GFAP for all participants receiving PET scans, as well as selected participants in a case-control design, and results are undergoing initial QC analysis. Selected publications over the last year are highlighted: Associations between cognitive and brain changes (Armstrong et., NeuroImage 2020): We investigated relationships between age-related changes in regional brain volumes and changes in domain-specific cognition in 836 BLSA participants with a mean follow-up of 4.1 years (maximum 23.1 years). We used bivariate linear mixed models to simultaneously model the longitudinal trajectories for each variable of interest and correlations among the random effects of these measures. Higher annual rates of memory decline were associated with greater volume loss in 14 VOIs primarily within temporal and occipital lobes. Verbal fluency decline was associated with greater ventricular enlargement and volume loss in 24 VOIs within frontal, temporal, and parietal lobes. Decline in visuospatial ability was associated with volume loss in 3 temporal and parietal VOIs. Declines in attention were associated with volume loss in 4 VOIs located within temporal and parietal lobes. Greater declines in executive function test were associated with greater ventricular enlargement and volume loss in 10 frontal, parietal, and temporal VOIs. Our findings highlight domain-specific patterns of brain atrophy that may contribute to individual differences in cognitive aging. Effects of age, sex and APOE genotype on default mode network connectivity and cognition (Shafer et al., Neurobiol Aging 2021). The default mode network (DMN) overlaps with regions showing early AD pathology. We examined age, sex, and APOE e4 carrier status as potential AD risk factors that may modify DMN connectivity and its relationship to cognition. 475 cognitively normal adults were studied with resting state functional MR (rsfMR). Analyses targeted total DMN connectivity, its anticorrelated network (acDMN), and the DMN-hippocampal component. The four main findings were: 1. In the APOE e3/e3 group, lower DMN and acDMN connectivity were observed with age. 2. Sex and e4 modified the relationship between age and connectivity for the DMN and hippocampus, with e4 vs. e3 males showing sustained or higher connectivity with age. 3. In the e3 group, age and sex modified connectivity-cognition relationships with the oldest participants having the most differential patterns due to sex. 4. e4 carriers with lower connectivity had poorer cognitive performance. Our results indicated that age, sex and APOE status together interact to influence brain function and function-cognition relationships. iSTAGING Consortium and Brain Charts of Aging (Habes et al. Alz and Dementia 2020): We are active participants in a consortium aimed at using machine-learning analytics in a large set of 10,216 harmonized MR scans (11 studies) to investigate links between brain aging, white matter disease, amyloid burden, and cognition. This large-scale collaborative project establishes brain charts with aging which enable the multidimensional characterization of individuals. Machine-learning tools were used to estimate scores reflecting brain-age, AD-like neurodegeneration, and white matter hyperintensities (WMHs). We used Brain Charts to measure and display the relationships of these signatures to cognition and molecular biomarkers of AD. We found that WMHs were associated with advanced brain aging, AD-like atrophy, poorer cognition, and AD neuropathology in both MCI/AD and cognitively normal subjects. WMHs were associated with doubling the likelihood of amyloid beta positivity after age 65. Brain aging, AD-like atrophy, and WMHs were better predictors of cognition than chronological age in MCI/AD. In addition to these highlights, our group has also used our neuroimaging and cognitive data to examine multimorbidity in relation to brain function (Beason-Held et al., 2021) and to extend studies of hearing loss by examining associations with DTI-based white matter microstructure (Armstrong et al., JAMA Otol 2020). Data generated by this project are also used by many intramural and extramural collaborators for methods development, including DTI metrics and PET partial volume correction, and in studies of the neural underpinnings of motor function, hearing loss, energetics, and sleep. They also are actively used through our participation in the Preclinical AD Consortium, led by Marilyn Albert of Johns Hopkins, and the iSTAGING consortium, led by Christos Davatzikos of the University of Pennsylvania, with several manuscripts at various stages of the review process.