ADMIRE Alzheimer’s disease Diagnosis by Multimodal Imaging of the Retina
Alzheimer’s disease Every 3 seconds someone in the world is diagnosed
people with dementia live at home, the disease also
with Alzheimer’s disease, the most common form
has a severe impact on the lives of their caregivers,
of dementia. More than 50 million people live with
which are usually close relatives.
dementia today. That number is expected to keep increasing dramatically as long as there are no ways to
Today, the global annual socio-economic costs
prevent, halt or cure the disease.
for dementia care are estimated at US$ 1 trillion (Alzheimer’s Disease International). These staggering
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Dementia is a major cause of disability in the elderly,
costs are predicted to bankrupt healthcare systems –
leading to high costs to society. As the majority of
unless we act now to halt the dementia pandemic.
The challenge One of the major contributions to the high failure
40% of global dementia cases could be prevented or at
rate in developing effective drugs for Alzheimer’s is
least delayed when taking 12 risk factors into account
the lack of techniques to screen people at risk and
(Livingston et al. 2020, The Lancet).
diagnose the early stages of the disease. Nowadays, someone with signs of dementia presenting Interventions are likely to be most effective when
at the memory clinic gets a first assessment based
provided early on: once neurodegeneration has started
on their family history, physical health, cognitive
and neurons are lost, the damage is irreversible. It is
functioning and sometimes genetic testing.
estimated that the first pathological changes in the brain occur several decades before the onset of clinical
In a next step, the diagnosis of Alzheimer’s disease can
symptoms, indicating a large ‘treatment gap’.
be made based on brain imaging (such as PET and MRI scans) and cerebrospinal fluid measurements.
It could be that some drugs that have failed in clinical
Brain imaging is expensive, while CSF measurements
trials so far are successful when given at an earlier
require an invasive lumbar puncture. Both are not
disease stage. To find out if this is the case, we need
very comfortable to patients and are not routinely
to find a much better way to identify presymptomatic
performed. Their scalability and usefulness for long-
patients and include them in clinical studies.
term follow-up of disease progression are limited. Moreover, they are not sensitive enough to detect
While waiting for successful treatments, we could
pathological changes at very early disease stages and
set up personalized prevention plans for people
offer a relatively low resolution.
identified at an early stage of the disease. We know today that adopting a healthy lifestyle helps reduce the
There is currently no appropriate diagnostic tool
risk of dementia. A recent study even found that up to
available to widely screen populations at risk.
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Our solution: Alzheimer’s diagnosis via multimodal imaging of the retina (ADMIRE) Our project is based on the idea that the eye can be
In contrast to the brain, the retina can be studied
considered as a ‘window to the brain’. The retina
directly, in a non-invasive way, during a routine eye
in the back of the eye is the only visible part of our
scan in the ophthalmologist’s practice. Eye exams
central nervous system and it shares many features
hold great potential for a more affordable, more rapid
with the brain.
and less invasive diagnosis of Alzheimer’s disease.
Alzheimer’s disease is characterized by an abnormal
To enable the detection of amyloid-beta proteins,
buildup of a protein called amyloid-beta in the brain.
our interdisciplinary team of clinicians, basic
This protein appears as small particles that have toxic
scientists and engineers equipped a traditional
effects on brain cells and clump together in ‘plaques’.
ophthalmologist’s camera with a novel line of technology: hyperspectral imaging.
Investigations in Alzheimer’s disease models and post-mortem donated eyes from patients indicate that increasing amounts of amyloid-beta are also present in the retina as the disease progresses. Possibly related to that, more than half of all patients eventually develop problems with vision. Certain pathological changes may even be detectable in the retina before they have appeared in the brain. retina
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(Figure: Shutterstock)
The technique is based on the reflection (scatter) of a light beam when it hits an amyloid-beta particle, much like how a rainbow is formed when sunlight hits rain drops. Here’s how it works:
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Like any camera, a hyperspectral camera captures the light that is reflected by objects. Where regular cameras divide the reflecting light in three main color groups (red, blue and green), a hyperspectral camera has a much higher sensitivity. It can distinguish tens to hundreds of different light wavelengths – even from outside our visible color
(Figure: Hadoux et al., 2019)
spectrum. •
At imec, we have successfully developed special
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The hyperspectral camera allows to pick up a
hyperspectral filters that only let light of
specific ‘signature spectrum’ that indicates the
specific wavelengths pass. Thanks to our expertise
presence and amount of amyloid-beta proteins –
in microchip technology, we managed to integrate
or any other object of interest.
thousands of these specific filters onto tiny chips. We found that arranging the filters in a mosaic pattern makes it possible to capture a lot of information from one single snapshot image in just a few milliseconds.
The eye can be considered as a ‘window to the brain’. 5
imec hyperspectral filters on microchips
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Next, we partnered up with camera building companies to integrate the chips into a userfriendly compact camera. The result is a small box of 10 cubic centimeters that can be easily added onto the microscope that ophthalmologists use during a routine eye exam.
XIMEA snapshot hyperspectral camera with imec mosaic hyperspectral sensors
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Current status of the project and outlook Our team members from the Research Group
technology. Our new tool could become widely used
Ophthalmology (KU Leuven, UZ Leuven) have
as a low-cost, superfast and non-invasive alternative
recently completed a proof-of-concept study
for today’s diagnostic tests.
(Lemmens et al. 2020) on 39 people: some healthy, some with a diagnosis of Alzheimer’s disease. After
In the next steps we will further optimize the technical
training a machine-learning algorithm with
setup and the hyperspectral sensors to increase the
images obtained from the snapshot hyperspectral
diagnostic accuracy even further.
camera, it could successfully distinguish Alzheimer’s patients from controls with 75% accuracy.
In parallel, our researchers from the Animal Physiology and Neurobiology division (KU Leuven)
This number increased further when combined
apply hyperspectral retinal imaging in preclinical
with another type of retinal imaging (thus making
studies.
the method ‘multimodal’): optical coherence tomography, or OCT. This technique is commonly used by ophthalmologists to look at the whole retina in detail. For instance, it allows them to measure the thinning of the retinal nerve fibers, a known sign of neurodegeneration. These positive first clinical results illustrate the potential of retinal imaging in Alzheimer’s diagnosis and justify further development of the hyperspectral
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2020 First proof-of-concept study in patients
In mouse models of Alzheimer’s disease, we confirmed
Besides Alzheimer’s, several other neurodegenerative
that amyloid-beta builds up in the retina and that
diseases can be imaged at the level of the retina. In
hyperspectral imaging can be used as a sensitive
future research phases, we will expand our scope
method to quantify the aggregations in the earliest
to include Parkinson’s disease, Lewy body
disease stages (Vandenabeele et al. 2020).
dementia and eye diseases such as glaucoma. Also for those diseases, the potential of hyperspectral
This offers unique opportunities for preclinical
imaging and retinal biomarkers will be assessed in
research into the early stages of Alzheimer’s disease
preclinical and clinical studies.
and studies screening for candidate drugs.
Our roadmap 2021
2022
2023
2024
Preclinical studies in Alzheimer mouse models to study underlying molecular and cellular pathological correlates Cross-sectional and longitudinal clinical studies with larger patient cohorts (Alzheimer’s, Parkinson’s, Lewy body dementia) to validate the specificity and sensitivity of the hyperspectral signal Fine-tuning of retinal acquisition protocols
Multimodal data integration and advanced computer models
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Our new tool could become widely used as a low-cost, superfast and non-invasive alternative for today’s diagnostic tests for several diseases. Prof. Dr. Ingeborg Stalmans, project coordinator
Further reading • https://www.imechyperspectral.com/en/articles/could-check-ophthalmologist-lead-better-treatmentalzheimers-disease (article by imec hyperspectral) • Christinaki et al. 2021 (Clin Exp Optom) Retinal imaging biomarkers of neurodegenerative diseases (review article) • Lemmens et al. 2020 (Alzheimer’s Research & Therapy) Combination of snapshot hyperspectral retinal imaging and optical coherence tomography to identify Alzheimer’s disease patients (proof-of-concept study) • Lemmens et al. 2020 (Translational Vision Science & Technology) Hyperspectral Imaging and the Retina: Worth the Wave? (review article) • Vandenabeele et al. 2020 (Acta Neuropathologica Communications) The AppNL-G-F mouse retina is a site for preclinical Alzheimer’s disease diagnosis and research (preclinical study) For the latest overview of our publications, go to www.missionlucidity.com/publications 10
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Our interdisciplinary team of experts ↗ Prof. Dr. Ingeborg Stalmans ophthalmologist, project coordinator Prof. Dr. Lies De Groef neurobiologist ↑
Prof. Dr. Rik Vandenberghe ↙ neurologist and head of the memory clinic
↗ Prof. Dr. Mathieu Vandenbulcke geriatric psychiatrist
↘ Prof. Dr. Wim Vandenberghe neurologist and head of the movement disorders clinic
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Watch a video of our researchers describing the ADMIRE project
↘ Prof. Dr. Matthew Blaschko electrical engineer and machine learning expert
↘ Prof. Dr. Lieve Moons neurobiologist
↗ Dr. Murali Jayapala, system science engineer
Prof. Dr. Bart De Strooper ↖ molecular biologist
Other academic partners include Prof. Dr. Peter van Wijngaarden (University of Melbourne, Australia) and Prof. Dr. Gauti Johannesson (Umeå University, Sweden).
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Personalized genetic risk profile Translating individual risk to disease phenotypes and prevention
A human brain on a chip Re-creating neural circuits to stratify patients and identify new drug targets
Non-invasive transcranial electrical stimulation Stimulating the brain to preserve cognitive function
Vascularized chip-based brain organoids Towards improved and humanized disease models
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Detecting disease by retinal imaging The eye as a window to the brain: early biomarkers in the retina
About Mission Lucidity Founded in 2018, Mission Lucidity is a partnership between four research institutes in Leuven, Belgium: imec, KU Leuven, University Hospitals Leuven and VIB. By leveraging the expertise of engineers, clinicians and scientists, combined with the backing of visionary donors, we aim to develop game-changing, scalable technology platforms and tools for neurodegeneration research. This will give the scientific community at large a unique opportunity to deliver scientific and medical breakthroughs. Our projects adopt a multi-angle approach: from zooming in on the cellular and intracellular level via technology development at nanoscale, to studying biomarkers and disease mechanisms in humans. Ultimately, our transformative technologies will allow us to answer longstanding questions and better understand, predict, diagnose and treat neurodegenerative diseases.
Visit www.missionlucidity.com/research to learn more about our projects.
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