Blood and brain gene expression trajectories mirror neuropathology and clinical deterioration in neurodegeneration
Abstract
Most prevalent neurodegenerative disorders take decades to develop and their early detection is challenged by confounding non-pathological ageing processes. For all neurodegenerative conditions, we continue to lack longitudinal gene expression data covering their large temporal evolution, which hinders the understanding of the underlying dynamic molecular mechanisms. Here, we overcome this key limitation by introducing a novel gene expression contrastive trajectory inference (GE-cTI) method that reveals enriched temporal patterns in a diseased population. Evaluated on 1969 subjects in the spectrum of late-onset Alzheimer’s and Huntington’s diseases (from ROSMAP, HBTRC and ADNI datasets), this unsupervised machine learning algorithm strongly predicts neuropathological severity (e.g. Braak, amyloid and Vonsattel stages). Furthermore, when applied to in vivo blood samples at baseline (ADNI), it significantly predicts clinical deterioration and conversion to advanced disease stages, supporting the identification of a minimally invasive (blood-based) tool for early clinical screening. This technique also allows the discovery of genes and molecular pathways, in both peripheral and brain tissues, that are highly predictive of disease evolution. Eighty-five to ninety per cent of the most predictive molecular pathways identified in the brain are also top predictors in the blood. These pathways support the importance of studying the peripheral-brain axis, providing further evidence for a key role of vascular structure/functioning and immune system response. The GE-cTI is a promising tool for revealing complex neuropathological mechanisms, with direct implications for implementing personalized dynamic treatments in neurology.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 28, 2020
- Source ID
- 10.1093/brain/awz400
Entities
People
- Ahmed F Khan
- Amir H Shirazi
- Quadri Adewale
- The Alzheimer’s Disease Neuroimaging Initiative*
- Yasser Iturria-medina
Organizations
- Alzheimer's Association
- Alzheimer's Disease Neuroimaging Initiative
- Alzheimer's Drug Discovery Foundation
- BioClinica
- Brain Canada Foundation
- Bristol-Myers Squibb
- Canada First Research Excellence Fund
- Chiron Corporation
- Eli Lilly and Company
- Foundation for the National Institutes of Health
- Illinois Department of Public Health
- Johnson & Johnson Pharmaceutical Research and Development
- McGill University
- Merck & Co.
- Meso Scale Diagnostics (United States)
- National Institute of Biomedical Imaging and Bioengineering
- National Institute on Aging
- National Institutes of Health
- Northern California Institute for Research and Education
- Pfizer
- Takeda Pharmaceutical Company
- United States Department of Defense
- University of California
- University of Southern California