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expert reaction to two papers on dementia looking at the blood-brain barrier and brain inflammation in mice

Two papers, published in Science Translational Medicine, report that Dementia has been reversed in mice with a drug that reduces brain inflammation.

 

Prof Robert Howard, Professor of Old Age Psychiatry, UCL, said:

“The two papers are interesting, but the claim made in the accompanying press release statement, that “Dementia has been reversed for the first time”, is both misleading and irresponsible.

“One paper shows that an experimental model of brain ageing, in which the serum protein albumin is infused directly into the brain of rodents, can be somewhat ameliorated by blocking a signalling pathway in the brain.  The other is a demonstration that a specific brain wave pattern, sometimes seen in patients with Alzheimer’s disease, is also seen in rats who have had albumin infused into their brains.

“While these papers add to our knowledge about potential models and mechanisms of brain ageing and how these might be experimentally manipulated in rodent models, they do not directly tell us anything about dementia or how we might prevent or treat the condition.

“The sad truth is that we do not have any treatments that can slow or reverse the course of dementia.  The field is desperate for a discovery that can change this.  It’s incredibly unhelpful if people with dementia, their families and medical attendants hear unsupported and over-promised prospects for treatments.”

 

Prof John Gallacher, Director of Dementias Platform UK, University of Oxford, said:

“These papers provide evidence on how blood brain barrier leakage can affect inflammation in the brain, leading to accelerated brain ageing.  However, reliance on rodent models for the experimental data means the extent to which this is linked causally in humans to specific brain pathologies such as Alzheimer’s disease remains unclear.  Although reducing the inflammatory load on the brain will likely deliver benefit, the reversal of dementia remains some years away.”

 

Dr Mark Dallas, Associate Professor of Pharmacology, University of Reading, said:

On the paper by Senatorov Jr et al:

“This interesting study examined the ageing brain and the breakdown of the physical barrier that protects the brain from the periphery.  In old mice this barrier becomes weakened, which allows for chemicals to enter the brain and cause damage.  In addition, they highlight the role that the brain’s supporting cells play in protecting nerve cells from this damage, and importantly the ability to alter these detrimental changes through administration of a drug and biochemical interventions.  It should be noted that ageing is not dementia, and while we know that some of these changes also occur in dementia it is unclear to what extent the pathways revealed here are able to impact on specific dementia related changes in brain function.

On the paper by Milikovsky et al:

“We have known about the changes in brain electrical activity and the links between epilepsy and dementia for a while.  This research takes the story further and examines specific patterns of activity and the ability to induce a type of activity associated with disruption of the blood brain barrier.  This study reveals a similar increase in a pattern of activity in animals with epilepsy, dementia and those treated with a chemical that leaks through the blood brain barrier in these conditions.  Here the emphasis is on how the activity patterns could be used to diagnose underlying brain disease, through non-invasive electric recordings.”

 

Dr James Pickett, Head of Research at Alzheimer’s Society, said:

“This study does shed some more light on how the brain ages, but as the mice studied did not have dementia it’s impossible to understand at this stage if these findings could help the 850,000 people living with dementia in the UK.

“Dementia research has long focused on targeting amyloid plaques in the brain that are seen in dementia.  Instead this study looks at the impact of inflammation on memory and thinking.  It’s an emerging exciting field, and we would welcome more dementia-specific research in this area which is why at Alzheimer’s Society, we are supporting a number of projects in this field”.

 

Dr Ian Maidment, Reader in Clinical Pharmacy, Aston University, said:

“Experiments in mice may not translate to humans; put another way just because a drug works in mice it doesn’t mean that it will work in humans.

“Over the last few years, many drugs for dementia that showed promise in animal studies failed to work in clinical trials in humans.

“Even if the drug is effective in humans it also needs to be safe.

“Therefore tests would also be required to determine if the drug was safe in humans.

“Whilst this may be a promising area, it would usually be premature to conclude solely from animal studies, that you might a have “cure” for diseases, such as dementia, in humans.”

 

Prof Diego Gomez-Nicola, Associate Professor in Neuroscience, University of Southampton, said:

“These two exciting reports highlight the ability of transient inflammation-related changes to alter cognitive function.  This work is important, as it demonstrates transient changes to the permeability of the blood-brain barrier in dementia, and how these drive local changes in the brain.  However, the interpretations of this study must be raised with caution, as mostly relying on data from mouse models.

“The role of the blood-brain barrier in influencing the brain’s inflammatory tone is one of the components of neuroinflammation, but it is important to remark that the main driver of this response in dementia is the main resident innate immune cell, the microglia.  Therefore, more research would be needed to understand how these transient changes impact the main immunocompetent population already engaged in driving the neuroinflammatory response, as these are accepted as central hubs of neuroinflammation.  Also, these transient changes in blood-brain barrier permeability would suggest access of systemic inflammatory solutes, and perhaps inflammatory cells, to the brain tissue, aspects not fully explored here but with high interest for future studies.

“Overall, these studies add to a body of knowledge supporting the impact of inflammation on dementia, and provides promising targets for future clinical studies.”

 

Prof Tara Spires-Jones, UK Dementia Research Institute Programme Lead, and Deputy Director of the Centre for Discovery Brain Sciences, University of Edinburgh, said:

“The statement from the press release that “Dementia has been reversed for the first time with a drug that reduces brain inflammation” is not accurate.  Neither paper demonstrated reversal of dementia in humans.  The paper by Dr Kaufer and colleagues from Berkely shows that reducing inflammation prevents cognitive impairment in aged mice and in mice modelling damage to the blood brain barrier.  The paper by Friedman and colleagues from Ben-Gurion University of the Negev showed altered brain activity in people with Alzheimer’s disease and epilepsy and in rodent models of these diseases, but they do not report any anti-inflammatory treatments of humans or rodents.  The data in these papers will be useful for other scientists, but will require much more work to determine if this approach will be useful for people living with dementia.

“It is important to note that there have already been clinical trials aimed to reduce brain inflammation in people with Alzheimer’s disease that have so far failed.”

 

Prof David Curtis, Honorary Professor, UCL Genetics Institute, said:

“So far as I can see this study is not really very relevant to the common mechanisms for dementia which we observe in humans.  It seems that they have made an intervention which impairs brain function in rodents and then inhibited that mechanism to result in improved functioning.  This is very far from being able to, for example, inhibit the mechanisms which underly Alzheimer’s disease or any other specific forms of dementia.

“There are plenty of previous studies which show similar effects in rodent models and many of these do target the processes which cause Alzheimer’s disease.  However to date it has proved difficult to translate these successful trials of treatments in animal models into novel drugs which can slow disease processes in humans.  I’m afraid I don’t think this is something to get excited about.”

 

Dr Sara Imarisio, Head of Research at Alzheimer’s Research UK, said:

“A barrier between the blood and brain is an important protection against damage and infection, and faults in it have been implicated in diseases like Alzheimer’s.  This early-stage research, predominately carried out in mice, suggests that the immune system is activated when the blood-brain barrier fails and highlights a potential way to detect people with a leaky-blood brain barrier.  These findings will need to be followed up with more extensive research in people

“Alzheimer’s is complex and changes to the blood-brain barrier are just one aspect of the disease.  While this research in mice highlights a potential way to limit the impact of a leaky blood-brain barrier, this is unlikely to affect other brain changes driving damage in Alzheimer’s.  While this well-conducted research improves our understanding of early brain changes associated with ageing it does not suggest dementia has been reversed.

“Increasingly, scientists are focusing on the immune system as a way to potentially treat diseases like Alzheimer’s in future.  Taking intriguing findings like this forward will help in the search for new drugs that could be the key to treating these devastating brain diseases.”

 

*Paper 1: ‘Paroxysmal slow cortical activity in Alzheimer’s disease and epilepsy is associated with blood-brain barrier dysfunction’ by Dan Z. Milikovsky et al. was published in Science Translational Medicine at 19:00 UK time on Wednesday 4 December 2019.

 

Paper 2: ‘Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction’ by Vladimir V. Senatorov Jr et al. was published in Science Translational Medicine at 19:00 UK time on Wednesday 4 December 2019.

 

Declared interests

Prof Robert Howard: “No relevant conflicts of interest.”

Prof John Gallacher: “No conflicts of interest.”

Dr James Pickett: “No conflicts of interest, although we are supporting a number of projects in this field.”

Dr Ian Maidment: “No conflicts to declare.”

Prof Tara Spires-Jones: “I have no conflicts of interest with these papers.”

Prof David Curtis: “I have no conflict of interest.”

Dr Sara Imarisio: “No conflict of interests.”

None others received.

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