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A Local Accumulation Connected Spread Model of Neurofibrillary Tangle Propagation in Human Neocortex

Thursday, August 12, 2021

3:00 PM-5:00 PM

BIOMED PhD Thesis Defense
A Local Accumulation Connected Spread Model of Neurofibrillary Tangle Propagation in the Human Neocortex

Ian Andrew Kennedy, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University
Andres Kriete, PhD
Associate Dean for Academic Affairs
School of Biomedical Engineering, Science and Health Systems
Drexel University
Michael David Devous, Sr, PhD
Former VP, Imaging Development
Avid Radiopharmaceuticals

Alzheimer’s disease (AD) is a devastating neurodegenerative disease which affects approximately 6.2 million Americans and is expected to grow exponentially by 2050 as the population ages. Those with AD required 15.3 billion hours of care, most of which is unpaid care from family members, and cost, on average, almost $321,780 per person.

Current hypotheses on the mechanism of AD incorporate the combined role of two proteins: beta amyloid plaques and neurofibrillary tangles (NFTs). They are hypothesized to work together in the amyloid cascade hypothesis to bring about the toxic effects of disease. Tau protein normally stabilizes microtubules in the central nervous system, but their phosphorylation causes destabilization and the formation of tangles. The direct cause of this phosphorylation is unknown, but amyloid plaques are believed to play a role. These tangles disrupt neuron function and synaptic communication. Unable to communicate these cells die. The tangles propagate via synaptic connections, resulting in regional atrophy which follows the spread of NFTs. Cognitive decline increases as the disease worsens, generally thought to correlate with increasing spread of NFTs. Currently, AD is only able to be definitively diagnosed at autopsy, complicating the understanding the disease and validation of therapeutic clinical trials. The advent of amyloid- and tau-specific PET tracers in conjunction with other imaging biomarkers has led to a hypothetical model of the progression of AD.  However, the mechanism of propagation of disease is still not well defined.

Quantitative and qualitative descriptions of the accumulation and advancement of NFTs throughout the cerebrum from both in vitro pathologic staining and in vivo flortaucipir NFT PET imaging characterizes the propagation of NFTs by increasing local intensity and increasing spatial extent. Here we propose a local accumulation connected spread (LOCS) model of NFT propagation which naturally encompasses the intensity-extent phenomenon through a reaction-diffusion equation wherein the molecular mechanisms leading to tau accumulation in neurons represents the reaction and the expansion of tau with increasing disease stage along connected white matter trajectories is considered as a diffusion process.

We explored three objectives to better understand the utility of the LOCS model in predicting future NFT burden as represented by flortaucipir PET. First, we examined confounds inherent to flortaucipir PET and their effects on flortaucipir quantitation. Second, we generated a whole brain connectome to model the diffusion process and related harmonics of the connectome to flortaucipir uptake to understand concordance between connectivity and NFT burden. Third, we estimated parameters for LOCS using Bayesian inversion to incorporate the uncertainties inherent to flortaucipir quantitation and the LOCS model itself and predicted future NFT burden in a clinical trial population. The application of LOCS modeling may provide insight into the accumulation and propagation of NFTs as represented by FTP PET throughout the cerebrum as well as the development of novel, tailored endpoints for AD therapeutic trials.

Contact Information

Natalia Broz

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