Biomarker presentation, amyloid status, and connectivity between the prefrontal cortex and hippocampus in studies of clinical Alzheimer’s disease/dementia
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Abstract
Through rigorous research over the past 100 years, great strides have been made in identifying the neuropathological basis of Alzheimer’s disease (AD), its’ prognosis, and the onset of cognitive symptoms. Proteins such as amyloid-beta (Aβ) plaques and tau are recognized as primary biomarkers that define AD and neuroimaging methods have been developed to measure these proteins in vivo allowing for changes to be monitored in life. These advances have led to the view that AD is a continuum rather than one inclusive state. However, there remains a great deal about AD that is still not understood. Such ambiguities range from an imprecise understanding of the neuropathological events that result in dementia to remaining uncertainty as to why some older adults exhibit symptoms of dementia whereas other retain sharp cognitive abilities in old age despite similar underlying pathology.
In an effort to fill some of these gaps in our knowledge, the overarching goals of the work in this dissertation were to disambiguate some of these nuances by examining neurobiological features of AD in living older adults. Data for the first two studies was collected from older adults enrolled in the nationwide Alzheimer’s Disease Neuroimaging Initiative (ADNI) and data in the third study came from participants aged 50 years and older enrolled in a cohort study at the Boston University Alzheimer’s Disease Research Center (BU-ADRC).
In the first study, our objective was to investigate links between brain structure, cognitive performance, and neuropathology in participants within the ADNI who identified as Black or African American (BoAA). Relatively little is known about dementia in this population so our goal was to assess if there would be an increase in AD biomarkers abnormalities between the three clinical syndrome groups: cognitively normal, mildly cognitively impaired (MCI), and dementia. Our findings supported this hypothesis as we found decreased cortical thickness in five of seven selected regions of interest (ROI), decreased hippocampal volume, increased white matter hyperintensities, worsened measures of cognition and function, decreased cerebrospinal fluid (CSF) measures of Aβ1-42 , and elevated measures of CSF tau between clinical syndrome groups.
In the next study, we utilized a different subset of ADNI participants to examine how crossing the threshold in Aβ burden from being amyloid negative (A-) to amyloid positive (A+) as measured on positron emission tomography (PET) scans may relate to other neuropathological AD biomarkers and cognition. To make this assessment, we identified two groups of ADNI participants: one who converted in Aβ burden from A- to A+ as measured by amyloid retention on [18F]-labeled florbetapir PET and another who did not convert (e.g. remained A-) over the same follow-up period. We found increased prevalence of APOE ε4, greater annualized percent volume loss in selected brain regions, and lower CSF Aβ1-42 in the amyloid converter group compared to the non-converter group. Amyloid ligand binding on florbetapir PET was also significantly different between the two groups on PET scans taken at two timepoints.
In the last study, we used diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) data from the BU-ADRC to assess the integrity of the cingulum bundle in participants cognitively ranging from normal to amnestic MCI to those with dementia. We found weakened integrity of the cingulum bundle in both dorsal and ventral circuits in participants with worsened cognitive function. Furthermore, we found relationships between diffusion metrics of the cingulum, volume of selected ROI, and measures of executive function and memory. The findings of this study show that age-related changes are likely present in a circuit that connects the prefrontal cortex to medial temporal regions of the brain and that weakening of structural connectivity is related to cognitive decline.
This collection of studies reiterates the complicated nature of AD. Factors such as race, genetics, transitions in biomarker status and perhaps yet to be discovered forms of pathology, all have the potential to modify the clinical presentation of AD. The studies completed in this dissertation help to advance our knowledge but more work is needed to solidify our understanding of the basis of AD.