The pathologic determinants of in vivo cortical atrophy in neurodegenerative disease are not well understood due in part to the lack of magnetic resonance (MR) imaging close to death. Resolving this relationship is necessary for addressing the utility of quantitative brain imaging as an in vivo marker for disease severity and progression. Primary progressive aphasia (PPA) is a clinical language dementia syndrome that provides an ideal model for exploring the relationship between cortical atrophy and underlying pathology because it is associated with a signature pattern of asymmetric atrophy concentrated in the left hemisphere language network. This relatively focal pattern of peak atrophy allows for within-subject comparisons between damaged and relatively spared regions (e.g., left vs. right hemisphere; language vs. memory-related regions). PPA can be caused by either Alzheimer disease (AD) pathology or frontotemporal lobar degeneration pathology with a left-hemisphere dominant distribution. Amyloid- plaques (APs) and neurofibrillary tangles (NFTs) are the hallmark pathologic features of AD that are known to coincide with neuronal and synaptic loss and accumulation of activated microglia. The relationships among these markers have not been characterized in PPA with AD pathology (PPA-AD), but will be examined in this project. Specifically, Aim 1 will determine the extent and severity of cortical atrophy in five language and two non-language regions (subserving memory and visual sensation) of PPA-AD participants who had structural MR scans within 2.5 years of death.
Aim 2 will quantify NFT, AP, activated microglia, neuron, and synapse densities in bilateral whole-hemisphere sections in the same regions and PPA-AD participants investigated in Aim 1 to determine the relationships among histologic markers, and their associations to in vivo measures of cortical atrophy. Our preliminary findings are consistent with our hypotheses and show that PPA-AD displays a leftward asymmetry of cortical atrophy in temporal and parietal language regions that corresponds to the highest densities of NFTs and lower densities of neurons. Combined results from this project will identify relationships among neurodegenerative features in order to discern the histopathologic basis of cortical degeneration underlying cognitive decline in PPA-AD.

Public Health Relevance

Primary Progressive Aphasia (PPA) is a clinical dementia syndrome caused by heterogeneous neuropathology that contributes to severe language impairments and asymmetric cortical atrophy concentrated in specialized regions of the language dominant (typically left) hemisphere. The proposed experiments will analyze PPA subjects with Alzheimer disease pathology to determine which histopathologic marker accumulates with greatest density in regions of the fewest neuronal markers and the most cortical atrophy measured close to death. Identifying these spatial relationships in the same subjects will provide critical insight into the neurobiological underpinnings of cortical atrophy, and its utility as an in vivo biomarker of disease severity in PPA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS095652-02
Application #
9356328
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Corriveau, Roderick A
Project Start
2016-09-01
Project End
2018-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611