Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CONNECT (Connecting neuronal network activity with regional specificity for Alzheimer pathology: a multi-modal neuroimaging approach)

Teaser

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...

Summary

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 (first images were made in 2013 in Boston). 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 is so far on schedule and has achieved most of its objectives and milestones with relatively minor deviations. 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.

Work performed

Due to overlap in funding the project was delayed with one year. During this time several other researchers worked on the relationship between neuronal activity and protein patterns. Therefore, it was decided to first work on the second aim, the locus coeruleus imaging, as this is very novel. In the meantime, the researcher worked on learning PET-data analyses and investigating spatial patterns of tau proteins along the lifespan. These analyses will facilitate the integration with the neuronal activity data, and by switching the order of the projects, the researcher would have access to longitudinal data (instead of only cross-sectional).
The researcher started in 2018 working on locus coeruleus imaging. Due to a magnet defect the 7T MRI was not operational. 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 126 healthy older individuals, 30 healthy younger individuals, 17 patients with (prodromal) AD and 14 preclinical AD patients with autosomal dominant AD due to a PSEN1-E280A mutation. As the tau tracer does not provide reliable signal in the locus coeruleus (due to off-target binding to neuromelanin), the researcher associated locus coeruleus MR-contrast (indication of neuromelanin cell density) to age, Aβ and tau pathology. The results showed that lower locus coeruleus contrast showed an inverted U-curve with age, consistent with postmortem studies. Furthermore, locus coeruleus contrast was related to both Aβ and tau pathology (Aim 2, deliverable 2 in the grant). In addition, in the asymptomatic individuals carrying the PSEN1-E280A genotype, the researcher also observed relationships between locus coeruleus contrast, tau pathology and memory performance. The results of the healthy individuals were presented at the Alzheimer’s Association International Conference in 2018 in Chicago. The results on the early-onset AD cases is submitted for presentation at the Alzheimer’s Association International Conference in 2019.
Furthermore, the researcher worked on investigating patterns in tau and Aβ along the lifespan in 369 individuals (38-93 years of age) by looking at asymmetry patterns in both proteins and relating this age, sex, handedness and cognition. Understanding asymmetry patterns of A or tau and their possible interaction can increase our knowledge of the biological mechanisms underlying clinical variability in AD. The researcher found that with greater age asymmetry in A and tau showed a frontal right-bias and posterior left-bias (Aim 1, deliverable 3 in the grant). Interestingly, these patterns are consistent with the evolutionary defined morphology and associated functional specialization of the brain. In the next steps it will be important to understand the relationship to neuronal activity: is neuronal activity driving these patterns? (Aim 1) In addition, the researcher observed that greater covarying asymmetry between A and tau in temporal regions is negatively associated with amyloid-related memory performance, again consistent with the functional specialization of the temporal lobe (Aim 3, deliverable 4 in the grant). The researcher presented these findings at the Alzheimer’s Imaging Conference at Chicago in 2018 and will soon submit the manuscript.

Final results

The researcher had the opportunity to collaborate to expand her knowledge on PET processing and extend her international network. In addition, the researcher is now relating longitudinal neuronal activity data to longitudinal measures of tau and Amyloid to understand their temporal and spatial patterns (final parts of Aim1 and 3). The analyses of this data are expected to be finished in the fall of 2019 (Deliverable 1 and 4).
At a societal level, the impact of visualizing the patterns of tau is expected to be more important than that of amyloid deposition, as it relates more closely to cognition and therefore can improve early diagnostics and define markers for interventions.
The researcher has conveyed her findings to the general audience (participants of the Harvard Aging Brain Study; students; newspaper) and will continue to disseminate her results in the future. In addition, so far, new collaborations are emerging with several research institutes in Germany, the UK, Denmark, Belgium and the USA leading to exciting new future projects, exchange of young researchers and position papers. To bring her acquired expertise to the European research area, the researcher is now starting up a study on biomarkers and locus coeruleus imaging at Maastricht University with intramural support.

Website & more info

More info: http://nmr.mgh.harvard.edu/lab/harvardagingbrain.