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Connecting neuronal network activity with regional specificity for Alzheimer pathology: a multi-modal neuroimaging approach

Periodic Reporting for period 2 - CONNECT (Connecting neuronal network activity with regional specificity for Alzheimer pathology: a multi-modal neuroimaging approach)

Reporting period: 2019-01-01 to 2019-12-31

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.
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. The researcher optimized a specific method to obtain good brainstem contrast from 3T MR images. Using these existing high-resolution images, the locus coeruleus could be identified in healthy older individuals, healthy younger individuals, patients with (prodromal) AD. The researcher demonstrated that lower integrity of the locus coeruleus was associated with tau accumulation similar to the autopsy staging work (Objective 2). 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 (Objective 1). Finally, the researcher was able to relate changes in locus coeruleus integrity to greater cognitive decline in the context of Alzheimer’s disease, confirming its relevance to both the pathology and symptomatology (Objective 3).Furthermore, the researcher investigated patterns in tau and Aβ along the lifespan by looking at asymmetry in both proteins. Understanding asymmetry patterns of Aβ or tau can increase our knowledge of the biological mechanisms underlying clinical variability in AD. The researcher found that with greater age asymmetry in Aβ and tau showed a frontal right-bias and posterior left-bias (Aim 1). Interestingly, these patterns are consistent with the functional specialization of the brain. In addition, the researcher observed that greater covarying asymmetry between Aβ and tau in temporal regions is negatively associated with amyloid-related memory performance, consistent with the functional specialization of the temporal lobe (Aim 3). The results were presented at the AAIC in 2018 and 2019; HAI 2020; Charles River Association for Memory Meeting in 2019; Locus coeruleus imaging 2019. Knowledge was disseminated via interviews, a Dutch summary for psychiatrists, educational evenings for the general population and study participants; workshops for students and two manuscripts are submitted for publication (one more in preparation).
The researcher was able to incorporate analyses that were initially considered as future perspectives (locus coeruleus activity during a face-name association task). These analyses provide a good opportunity to replicate and validate the initial findings using a different method. The researcher also expanded her training goals of learning PET processing and analyses to include the FDG-tracer.
The results of this project do contribute to the cumulative conclusion in the field that Alzheimer’s disease is a complex disease, most likely finding its origin early in life and with many biological factors interacting.In addition, these findings suggest that locus coeruleus imaging may be a promising marker of Alzheimer's disease related processes. At a societal level, this is important as the Alzheimer field is moving to earlier intervention, which requires good markers that can predict who is likely to progress.
The researcher has achieved all training objectives, is actively working on transferring knowledge to Europe through workshops with junior researchers, publications and organising a world-wide professional interest area in locus coeruleus imaging. In the Netherlands, she is currently supported by intramural support and Alzheimer Nederland, allowing her to run a large-scale study combining novel MRI-methods with biomarker data.
A) Examples of locus coeruleus scans ; B) locus coeruleus versus age relationship