A century has been lost searching in the wrong places for a cure to Alzheimer’s disease (AD). But with the contribution of imaging, researchers may take huge strides towards identifying high-risk profiles to define cohorts for future drug trials. Experts will show how imaging the glymphatic system and integrating clinical and population imaging hold promise, in a New Horizons session today.

More than 100 years of research in AD treatment have failed to deliver successful results, mainly because therapy was given only to patients with clinical symptoms of dementia, according to Prof. Sven Haller from Geneva, Switzerland, who will chair the session.

“By then, 50% of the neurons are lost. For 80 years, we have given patients drugs, only too late. Even if the medication works, it will not help revitalise dead neurons,” he said.

The common confusion between AD and other forms of dementia has also cast a long shadow over therapeutic advances.

Figure 1: gMRI: After intrathecal injection of gadobutrol at the lumbar level, the patient is followed with multiple T1-volume acquisitions up to 24-48 hours. The colour-coded scale indicates percentage increase in normalised signal units from baseline at T1-weighted scans. Contrast enhancement of CSF in the subarachnoid space is subtracted here. Previous studies have indicated that all brain regions enhance. Dimensional properties of the extra-vascular space can therefore be assessed and clearance rate from the brain (and CSF) can be compared between single subjects and patient cohorts (provided by Geir Ringstad; post-processing of images: Lars Magnus Valnes, Dept. of Mathematics, University of Oslo, Norway).

“Most people think AD and dementia are the same, but they are not. Not everybody who has dementia has AD. There are many other types of dementia, such as vascular dementia, a group of frontal dementias, and Lewy Body dementia, just to name a few. If you simply treat a person with signs of cognitive decline with AD medication, it may not work, as this person may not have Alzheimer’s,” he said.

There are different diseases and different disease subgroups. Drug development must take this diversity into account. “It is very unlikely that you will find a magic drug that will work in all patients.”

Getting early diagnosis is key and profiling is an interesting strategy. In Europe, trials are ongoing that run tests and assess risk factors, family history and genetics for preselection of high-risk people for drug trials. The European Prevention of Alzheimer’s Dementia Consortium (EPAD) is one such example.

Imaging can help recognise early signs of dementia and recent research has focused on visualising the human glymphatic system, which can provide important information on the disease, according to Prof. Geir Ringstad from Oslo, Norway.

“Molecular clearance from cerebrospinal fluid (CSF) may be compromised in dementia, and it can be measured,” he said.

Ringstad and his co-researchers have used repeated T1-weighted MRI scans throughout 24–48 hours and found that clearance of an intrathecally administered MRI contrast agent, gadobutrol, into the CSF is delayed from CSF and brain tissue in a dementia cohort with normal pressure hydrocephalus. This was done in comparison to a younger reference group under work-up for other CSF disorders such as leakage, hypertension and cysts.

Figure 2: Multiparametric MR protocol allowing for the assessment of brain structure and atrophy, various markers of neurovascular diseases and functional brain perfusion in one single imaging session (provided by Sven Haller).

These results show that there is a sign of reduced ‘brain wash’ in patients with dementia, said Ringstad, who has since called this exam glymphatic MRI (gMRI). “Since gadobutrol given via CSF enters from surface the compartment outside blood vessels in all brain regions and is not excreted into vessels, it is suitable for tracing the same extra-vascular excretion pathways we assume are relevant for neurotoxic molecules with a role in neurodegeneration, such as amyloid-beta and tau protein,” he said.

Ringstad’s ambition is now to diagnose reduced craniospinal molecular clearance rate in early or even pre-symptomatic dementia, which might enable early treatment. “Many neurodegenerative diseases are in principle proteinopathies, where accumulation of metabolic waste products in different parts of the brain may provoke a range of symptoms. Dementia categories overlap heavily, and it remains to be shown whether gMRI may improve differentiation between sub-types, or provide for other types of categorisation,” he said.

A major limitation for gMRI is that MRI contrast agents, even macrocyclic ones, are currently not approved for intrathecal use. Oslo University has therefore only performed gMRI in a study setting on clinical indication for work-up of CSF disorders and with special permission from the National Medicine Agency of Norway and Regional Ethical Committee. Last year, however, Ringstad published a safety study in the American Journal of Neuroradiology, reporting that short and long-term side effects for 0.5ml gadobutrol intrathecally were comparable to iodixanol, and with no serious events.

Proper clinical imaging assessment of patients is central to reaching early diagnosis, and integrating this information with population imaging would advance our knowledge of factors that influence brain health leading to dementia.

This is the goal of the Oxford Brain Health Centre, a recently opened memory clinic that sits between the university and the hospital. Prof. Clare Mackay, a neuroscientist who leads the new institution, hopes it will solve two problems that have long held back mental health care in the UK: inappropriate clinical assessment and lack of translational research.

“Most patients seen in psychiatric services are not being offered the imaging service that they should. At the same time, research studies often use an artificially refined population, so the things we develop in the research setting are not necessarily going to work in real life,” she said.

At the new clinic, every patient who undergoes a clinical imaging examination can now agree for his or her data to be shared for research purposes.

This model is an interesting solution in settings with low investment in public health and can help overcome healthcare inequality, by making high quality assessment available to everyone.

“There is a stigma associated with psychiatric patients, dementia and mental health in general. Those diseases are – wrongly – thought to be incurable. Accurate evaluation is a vital step towards finding a long-awaited cure. There are no disease modifying treatments for dementia, but until we assess people properly, we are not going to be able to put people into the right trials to test drugs as they come,” she concluded.

Note: For ECR 2020 in July, Professor Geir Ringstad was replaced by Dr. Maiken Nedergaard. Professor Clare Mackay was replaced by Professor Meike Vernooij.

LIVE
New Horizons Session
, Thursday, July 16, 15:30–16:30
NH 13 Alzheimer’s disease and neurodegeneration: visualising the invisible

  • Chairperson’s introduction
    Sven Haller; Geneva/CH
  • Visualising the human glymphatic system
    Maiken Nedergaard; Copenhagen/DK
  • PET as part of the biomarker toolbox for early clinical diagnosis of Alzheimer’s disease
    Javier Arbizu; Pamplona/ES
  • Imaging beyond beta-amyloid and tau: insights from high-field MRI
    Louise van der Weerd; Leiden/NL
  • Integrating population imaging with clinical imaging for the memory clinic
    Meike Vernooij; Rotterdam/NL
  • Live Q&A: Over 100 years of hype and hope in dementia and Alzheimer’s research: what lessons have we learned, and what are the future directions?

FURTHER READING

Benedictus MR, Leeuwis AE, Binnewijzend MA et al (2017) Lower cerebral blood flow is associated with faster cognitive decline in Alzheimer’s disease. Eur Radiol. 27(3):1169-1175: european-radiology.org/4450

Sgard B, Khalifé M, Bouchut A et al (2019) ZTE MR-based attenuation correction in brain FDG-PET/MR: performance in patients with cognitive impairment. Eur Radiol. doi: 10.1007/s00330-019-06514-z: european-radiology.org/5614

Tuzzi E, Hagberg GE, Balla D et al (2018) In-vivo and ex-vivo beta-amyloid load detection in Alzheimer’s Disease using R2* and quantitative susceptibility mapping (QSM) at ultra-high magnetic field: comparison to histology. ECR 2018 / C-3076: myESR.org/183076

Miras Ventura JA, Jiménez Coronel V, Pérez Naranjo P et al (2019) “Don’t forget the dementia!”: Differencial diagnosis in imaging it’s possible. ECR 2019 / C-0332: myESR.org/19332

Meijboom R, Steketee RME, Ham LS et al (2019) Exploring quantitative group-wise differentiation of Alzheimer’s disease and behavioural variant frontotemporal dementia using tract-specific microstructural white matter and functional connectivity measures at multiple time points. Eur Radiol. 29(10):5148-5159: european-radiology.org/6061