Neurobiological Basis of in vivo Cortical Atrophy in  Primary Progressive Aphasia Caused by Alzheimer’s Disease

Ohm, Daniel Timothy

doi:https://doi.org/10.21985/n2-acft-xm98

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Neurobiological Basis of in vivo Cortical Atrophy in Primary Progressive Aphasia Caused by Alzheimer’s Disease

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The brain is known to shrink in normal aging or neurodegenerative disease and yet the neurobiological underpinnings of the cortical atrophy remain elusive. The structural changes that represent cortical atrophy can be measured during life using the reliable and quantitative method known as magnetic resonance imaging (MRI). Primary progressive aphasia (PPA) is a language-based clinical syndrome characterized by focal left-lateralized cortical atrophy caused by multiple proteinopathies including Alzheimer’s disease (AD) and transactive DNA-binding protein of 43 kD (TDP) neuropathology. However, like other disorders characterized by cortical atrophy, the neuropathologic inclusions and cellular determinants of the cortical atrophy observed in PPA are not well understood. Previous work from our lab and others showed that neurofibrillary tau tangles (NFTs) and activated microglia (a neuroinflammatory marker) display regional densities that are closely associated with neurodegenerative processes and are consistent with the aphasic profile of individuals with PPA. In PPA participants with AD neuropathology (PPA-AD) that had MRI scans acquired close to death, we hypothesized that NFTs and activated microglia would be the primary neuropathologic contributors to neurodegeneration detected by MRI-based cortical atrophy or smaller densities of neurons. In a series of three related studies, the goal of the current dissertation was to examine the relationships between neuropathologic and cellular alterations in the postmortem brain, as well as their individual relationships with in vivo cortical atrophy in PPA. In Study 1, the neuropathologic basis of in vivo cortical atrophy was investigated in PPA-AD by determining if the magnitudes of regional atrophy were associated with the histopathologic hallmarks of AD neuropathology (NFTs and amyloid-beta plaques [APs]). Consistent with previous findings in PPA-AD and other AD clinical subtypes, only NFTs were found to be selectively associated with the greatest cortical atrophy measured in the left language regions in PPA-AD. In Study 2, activated microglia were exclusively quantified in the white matter in order to characterize the unique distribution of the neuroinflammatory marker and determine its association with cortical atrophy in two PPA pathologic subtypes (PPA-AD and PPA-TDP). The results indicated that while greater densities of activated microglia were related to regions of greater gray matter atrophy in PPA, this relationship was not consistently observed within individual PPA pathologic subtypes. Finally, in Study 3, the cellular determinants of in vivo cortical atrophy were examined in PPA-AD. This investigation involved the quantification of microglial subtypes (hypertrophic and ramified) potentially serving different roles in inflammation and disease progression and comparing each subtype to densities of neurons, AD neuropathology, and regional atrophy. Greater cortical atrophy was found to be associated with smaller densities of ramified microglia. Further analysis was carried out on a subset of regions in the PPA-AD cohort to determine how pathologic changes in white matter were related to cellular and neuropathologic changes in the gray matter. The results indicated that not only were NFTs and activated microglia (in gray and white matter) related to each other, each of these pathologic markers displayed a negative relationship with neurons as well. These multidisciplinary studies provided new insight into the histopathologic basis of in vivo cortical atrophy in PPA-AD by showing that NFTs displayed significant relationships with microglial activation, neurodegeneration, and cortical atrophy in PPA-AD. Therefore, similar to findings in amnestic AD, NFTs and neuroinflammation likely serve significant roles in the neuropathologic change and neurodegenerative processes that lead to the impaired cognition characteristic of the PPA clinical profile.

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