As the world’s population is aging, the prevalence of Alzheimer’s disease (AD), the most common form of dementia, is estimated to triple by 2050. The exact cause of AD remains poorly understood. To date, disease models have mainly focused on the role of two proteins that accumulate in the brain: amyloid plaques, accumulations of extracellular Abeta (Aβ) peptides, and neurofibrillary tangles, an accumulation of the intracellular hyperphosphorylated tau protein. Postmortem studies have shown that the tau protein starts to accumulate early in life, around age 20 in the locus coeruleus – a tiny region hidden in the brainstem. As people age, tau pathology progresses to more medial temporal lobe regions, which are critical for memory functioning. Around that time (50-60 years of age), the Aβ protein accumulates and most likely both proteins interact and lead to detectable cognitive deficits. In addition, neuronal activity, in particular in the medial temporal lobe, may be causally related to the progression of pathology. These observations imply that AD pathology occurs 2-3 decades prior to its diagnosis and if we aim to halt or treat this disease, it will be necessary to understand the biological processes associated with the progression of the proteins earlier in life.
Using specific radioactive tracers, Aβ in the brain can be visualized during life. The in vivo visualization of the tau protein is a recent development. This development now allows us to investigate regional interactions among both proteins throughout life.
The overall objectives of this fellowship were intertwined with these recent development as well as with the need to better understand the lifelong biology of this disease in order to halt its progression.
The objectives:
1. To understand the contribution of tau pathology to the relationship between neuronal activity, amyloid deposition and memory performance.
2. To investigate tau pathology of the locus coeruleus using a novel PET tracer and high-field MRI.
3. To determine the “causal” interactions between functional activity (connectivity), amyloid and tau accumulation and memory performance by combining specific PET tracers,(high-field) fMRI with specific statistical modeling
The project has achieved its objectives and milestones with relatively minor deviations (minor delays in publication).
In summary, during this action, the researcher was able to image the locus coeruleus in vivo in humans. The locus coeruleus is a tiny structure in the brainstem and difficult to visualize, but at the same time it is important for Alzheimer’s disease as it is the first site of tau accumulation and modulates various cognitive functions and behaviours. Using these new developed methods, the researcher was able to show that lower integrity of the locus coeruleus was associated with tau accumulation similar to the autopsy staging work. In addition, greater cortical tau accumulation was associated with greater neuronal activity in the locus coeruleus, indicating that the mechanisms underlying the earliest tau propagation may be related to synaptic function and functional connectivity. Finally, the researcher was able to relate changes in locus coeruleus integrity, structurally and functionally, to greater cognitive decline in the context of Alzheimer’s disease, confirming its relevance to both the pathology and symptomatology of Alzheimer’s disease.The results of this projects are ultimately important for our understanding of the pathophysiological cascade of AD and may lead to a new biomarker that could improve the early detection of AD
The researcher’s training aims were: 1) to obtain expertise in Positron Emission Tomography 2) extend statistical knowledge and 3) establish an international network. These objectives were achieved.
