̽��ֱ�� of Cambridge - Association of British Neurologists

Ultra-powerful brain scanners offer hope for Parkinson’s disease patients

cjb250 — Tue, 17 May 2022 08:00:09 +0000

7T MRI scanners could be used to help identify those patients with Parkinson’s disease and similar conditions most likely to benefit from new treatments for previously-untreatable symptoms, say scientists.

Inflammation in the brain linked to several forms of dementia

cjb250 — Tue, 17 Mar 2020 00:14:10 +0000

Inflammation is usually the body’s response to injury and stress – such as the redness and swelling that accompanies an injury or infection. However, inflammation in the brain – known as neuroinflammation – has been recognised and linked to many disorders including depression, psychosis and multiple sclerosis. It has also recently been linked to the risk of Alzheimer’s disease.

In a study published today in the journal Brain, a team of researchers at the ̽��ֱ�� of Cambridge set out to examine whether neuroinflammation also occurs in other forms of dementia, which would imply that it is common to many neurodegenerative diseases.

̽��ֱ��team recruited 31 patients with three different types of frontotemporal dementia (FTD). FTD is a family of different conditions resulting from the build-up of several abnormal ‘junk’ proteins in the brain.

Patients underwent brain scans to detect inflammation and the junk proteins. Two Positron Emission Tomography (PET) scans each used an injection with a chemical ‘dye’, which lights up special molecules that reveal either the brain’s inflammatory cells or the junk proteins.

In the first scan, the dye lit up the cells causing neuroinflammation. These indicate ongoing damage to the brain cells and their connections. In the second scan, the dye binds to the different types of ‘junk’ proteins found in FTD.

̽��ֱ��researchers showed that across the brain, and in all three types of FTD, the more inflammation in each part of the brain, the more harmful build-up of the junk proteins there is. To prove the dyes were picking up the inflammation and harmful proteins, they went on to analyse under the microscope 12 brains donated after death to the Cambridge Brain Bank.

“We predicted the link between inflammation in the brain and the build-up of damaging proteins, but even we were surprised by how tightly these two problems mapped on to each other,” said Dr Thomas Cope from the Department of Clinical Neurosciences at Cambridge.

Dr Richard Bevan Jones added, “There may be a vicious circle where cell damage triggers inflammation, which in turn leads to further cell damage.”

̽��ֱ��team stress that further research is needed to translate this knowledge of inflammation in dementia into testable treatments. But, this new study shows that neuroinflammation is a significant factor in more types of dementia than was previously thought.

“It is an important discovery that all three types of frontotemporal dementia have inflammation, linked to the build-up of harmful abnormal proteins in different parts of the brain. ̽��ֱ��illnesses are in other ways very different from each other, but we have found a role for inflammation in all of them,” says Professor James Rowe from the Cambridge Centre for Frontotemporal Dementia and a Fellow of Darwin College .

“This, together with the fact that it is known to play a role in Alzheimer’s, suggests that inflammation is part of many other neurodegenerative diseases, including Parkinson’s disease and Huntington’s disease. This offers hope that immune-based treatments might help slow or prevent these conditions.”

̽��ֱ��research was supported by Wellcome, the Medical Research Council, National Institute for Health Research Cambridge Biomedical Research Centre, Association of British Neurologists, Patrick Berthoud Charitable Trust, and the Lundbeck Foundation.

Reference
Bevan-Jones, WR & Cope, TE et al. Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum. Brain; 17 Mar 2020; DOI: 10.1093/brain/awaa033

Inflammation in the brain may be more widely implicated in dementias than was previously thought, suggests new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��researchers say it offers hope for potential new treatments for several types of dementia.

We predicted the link between inflammation in the brain and the build-up of damaging proteins, but even we were surprised by how tightly these two problems mapped on to each other

Thomas Cope

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Advances in brain imaging settle debate over spread of key protein in Alzheimer’s

cjb250 — Fri, 05 Jan 2018 00:05:06 +0000

An estimated 44 million people worldwide are living with Alzheimer’s disease, a disease whose symptoms include memory problems, changes in behaviour and progressive loss of independence. These symptoms are caused by the build-up in the brain of two abnormal proteins: amyloid beta and tau. It is thought that amyloid beta occurs first, encouraging the appearance and spread of tau – and it is this latter protein that destroys the nerve cells, eating away at our memories and cognitive functions.

Until a few years ago, it was only possible to look at the build-up of these proteins by examining the brains of Alzheimer’s patients who had died, post mortem. However, recent developments in positron emission tomography (PET) scanning have enabled scientists to begin imaging their build-up in patients who are still alive: a patient is injected with a radioactive ligand, a tracer molecule that binds to the target (tau) and can be detected using a PET scanner.

In a study published today in the journal Brain, a team led by scientists at the ̽��ֱ�� of Cambridge describe using a combination of imaging techniques to examine how patterns of tau relate to the wiring of the brain in 17 patients with Alzheimer’s disease, compared to controls.

Quite how tau appears throughout the brain has been the subject of speculation among scientists. One hypothesis is that harmful tau starts in one place and then spreads to other regions, setting off a chain reaction. This idea – known as ‘transneuronal spread’ – is supported by studies in mice. When a mouse is injected with abnormal human tau, the protein spreads rapidly throughout the brain; however, this evidence is controversial as the amount of tau injected is much higher relative to brain size compared to levels of tau observed in human brains, and the protein spreads rapidly throughout a mouse’s brain whereas it spreads slowly throughout a human brain.

There are also two other competing hypotheses. ̽��ֱ��‘metabolic vulnerability’ hypothesis says that tau is made locally in nerve cells, but that some regions have higher metabolic demands and hence are more vulnerable to the protein. In these cases tau is a marker of distress in cells.

̽��ֱ��third hypothesis, ‘trophic support’, also suggests that some brain regions are more vulnerable than others, but that this is less to do with metabolic demand and more to do with a lack of nutrition to the region or with gene expression patterns.

Thanks to the developments in PET scanning, it is now possible to compare these hypotheses.

“Five years ago, this type of study would not have been possible, but thanks to recent advances in imaging, we can test which of these hypotheses best agrees with what we observe,” says Dr Thomas Cope from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, the study’s first author.

Dr Cope and colleagues looked at the functional connections within the brains of the Alzheimer’s patients – in other words, how their brains were wired up – and compared this against levels of tau. Their findings supported the idea of transneuronal spread, that tau starts in one place and spreads, but were counter to predictions from the other two hypotheses.

“If the idea of transneuronal spread is correct, then the areas of the brain that are most highly connected should have the largest build-up of tau and will pass it on to their connections. It’s the same as we might see in a flu epidemic, for example – the people with the largest networks are most likely to catch flu and then to pass it on to others. And this is exactly what we saw.”

Professor James Rowe, senior author on the study, adds: “In Alzheimer’s disease, the most common brain region for tau to first appear is the entorhinal cortex area, which is next to the hippocampus, the ‘memory region’. This is why the earliest symptoms in Alzheimer’s tend to be memory problems. But our study suggests that tau then spreads across the brain, infecting and destroying nerve cells as it goes, causing the patient’s symptoms to get progressively worse.”

Confirmation of the transneuronal spread hypothesis is important because it suggests that we might slow down or halt the progression of Alzheimer’s disease by developing drugs to stop tau from moving along neurons.

Image: Artist's illustration of the spread of tau filaments (red) throughout the brain. Credit: Thomas Cope

̽��ֱ��same team also looked at 17 patients affected by another form of dementia, known as progressive supranuclear palsy (PSP), a rare condition that affects balance, vision and speech, but not memory. In PSP patients, tau tends to be found at the base of the brain rather than throughout. ̽��ֱ��researchers found that the pattern of tau build-up in these patients supported the second two hypotheses, metabolic vulnerability and trophic support, but not the idea that tau spreads across the brain.

̽��ֱ��researchers also took patients at different stages of disease and looked at how tau build-up affected the connections in their brains.

In Alzheimer’s patients, they showed that as tau builds up and damages networks, the connections become more random, possibly explaining the confusion and muddled memories typical of such patients.

In PSP, the ‘highways’ that carry most information in healthy individuals receives the most damage, meaning that information needs to travel around the brain along a more indirect route. This may explain why, when asked a question, PSP patients may be slow to respond but will eventually arrive at the correct answer.

̽��ֱ��study was funded by the NIHR Cambridge Biomedical Research Centre, the PSP Association, Wellcome, the Medical Research Council, the Patrick Berthoud Charitable Trust and the Association of British Neurologists.

Reference
Cope, TE et al. Tau Burden and the Functional Connectome in Alzheimer's Disease and Progressive Supranuclear Palsy. Brain; 5 Jan 2018; DOI: 10.1093/brain/awx347

Recent advances in brain imaging have enabled scientists to show for the first time that a key protein which causes nerve cell death spreads throughout the brain in Alzheimer’s disease – and hence that blocking its spread may prevent the disease from taking hold.

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Alzheimer's patients & carers

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