A Better Way to Predict the Progression of Alzheimer’s Disease

News Release
April 2019 | the Society of Nuclear Medicine and Molecular Imaging – New PET Imaging Biomarker Could Better Predict Progression of Alzheimer’s Disease

Reston, VA—Researchers have discovered a way to better predict progression of Alzheimer’s disease. By imaging microglial activation levels with positron emission tomography (PET), researchers were able to better predict progression of the disease than with beta-amyloid PET imaging, according to a study published in the April issue of The Journal of Nuclear Medicine.

According to the Alzheimer’s Association, an estimated 5.3 million Americans are currently living with Alzheimer’s disease. By 2025, that number is expected to increase to more than seven million. The hallmark brain changes for those with Alzheimer’s disease include the accumulation of beta-amyloid plaques. When microglial cells from the central nervous system recognize the presence of beta-amyloid plaques, they produce an inflammatory reaction in the brain.

“The 18-kD translocator protein (TSPO) is highly expressed in activated microglia, which makes it a valuable biomarker to assess inflammation in the brain,” said Matthias Brendel, MD, MHBA, at Ludwig-Maximilians-University of Munich in Germany. “In our study, we utilized TSPO-PET imaging to determine whether microglial activation had any influence on cognitive outcomes in an amyloid mouse model.”

Figure 2Longitudinal TSPO and Aβ PET and performance in behavioral testing. (A) Cortical TSPO PET and Aβ PET signal intensities of PS2APP mice at different ages are expressed as z scores relative to findings in age-matched C57BL/6 mice. Coronal and axial slices are projected on T1-weighted MRI template. (B) Progression of individual TSPO PET z scores and Aβ PET z scores in forebrain of PS2APP mice (n = 10) with age. (C) Differences between PS2APP and C57BL/6 (WT) mice for escape latency (sec) and traveled distance in pixels (pix) as WM readouts. Error bars represent SEM. *P < 0.01. **P < 0.001.

In the study, researchers compiled a series of PET images for 10 transgenic mice with beta-amyloid proteins and seven wild-type mice. TSPO PET imaging of activated microglia was conducted at eight, 9.5, 11.5 and 13 months, and beta-amyloid PET imaging was performed at eight and 13 months. Upon completion of the imaging, researchers then subjected the mice to a water maze in which the mice were to distinguish between a floating platform that would hold their weight and one that would sink. The tasks were performed several times a day during a 1.5-week period. Memory performance in the water maze was assessed by measuring the average travel time from the start point to a platform each day of training and by calculating the traveled distance at the last day of training. After completing the water maze task, immunohistochemistry analyses were performed for microglia, amyloid and synaptic density.

Transgenic mice with the highest TSPO PET signal in the forebrain or other areas associated with spatial learning tended to have better cognitive performance in the water maze, while beta-amyloid signals in the same areas of the brain showed no correlation to cognitive outcomes in the maze. Researchers found that an earlier microglial response to amyloid pathology in transgenic mice also protected synaptic density at follow-up. Specifically, transgenic mice with higher TSPO expression at eight months had much better cognitive outcomes in the water maze and higher synaptic density as confirmed by immunochemistry analyses.

“This study provides the first evidence that the level of microglial activation could be a far better predictor of current and future cognitive performance than beta-amyloid levels,” noted Brendel. “Keeping the limitations of mouse models in mind, it could be crucial to modify an individual’s microglial activation state to ameliorate future cognitive decline. We believe that a balanced microglia activation is crucial for prevention of cognitive impairment.”

The authors of “Early and Longitudinal Microglial Activation but Not Amyloid Accumulation Predicts Cognitive Outcome in PS2APP Mice” include Carola Focke, Maximilian Deussing, Claudio Schmidt, Simon Lindner, Franz-Josef Gildehaus, Leonie Beyer and Barbara von Ungern-Sternberg, Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany; Tanja Blume, Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany, and Center for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Munich, Germany; Benedikt Zott and Helmuth Adelsberger, Institute of Neuroscience, Technical  University of Munich, Munich, Germany; Yuan Shi and Mario M. Dorostkar, Center for Neuropathology and Prion Research, Ludwig-Miximilians-University of Munich, Munich, Germany, and DZNE-German Center for Neurodegenerative Diseases, Munich, Germany; Finn Peters, DZNE-German Center for Neurodegenerative Diseases, Munich, Germany; Gernot Kleinberger, Munich Cluster for Systems Neurology, University of Munich, Munich, Germany, and Biomedical Center, Biochemistry, Ludwig-Maximilians-University of Munich, Munich, Germany; Peter Bartenstein and Matthias Brendel, Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany, and Munich Cluster for Systems Neurology, University of Munich, Munich, Germany; Laurence Ozmen and Karlheinz Baumann, Roche Pharma Research and Early Development, F. Hoffman-La Roche Ltd., Basel, Switzerland; Christian Haass, DZNE-German Center for Neurodegenerative Diseases, Munich, Germany, Munich Cluster for Systems Neurology, University of Munich, Munich, Germany, and Biomedical Center, Biochemistry, Ludwig-Maximilians-University of Munich, Munich, Germany; Jochen Herms, Center for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Munich, Germany, DZNE-German Center for Neurodegenerative Diseases, Munich, Germany, and Munich Cluster for Systems Neurology, University of Munich, Munich, Germany; Axel Rominger, Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany, Munich Cluster for Systems Neurology, University of Munich, Munich, Germany, and Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.

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For more information or to schedule an interview with the researchers, please contact Rebecca Maxey at (703) 652-6772 or 
rmaxey@snmmi.org.  Current and past issues of The Journal of Nuclear Medicine can be found online at http://jnm.snmjournals.org.

About the Society of Nuclear Medicine and Molecular Imaging

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and medical organization dedicated to advancing nuclear medicine and molecular imaging, vital elements of precision medicine that allow diagnosis and treatment to be tailored to individual patients in order to achieve the best possible outcomes.

SNMMI’s more than 17,000 members set the standard for molecular imaging and nuclear medicine practice by creating guidelines, sharing information through journals and meetings, and leading advocacy on key issues that affect molecular imaging and therapy research and practice. For more information, visit www.snmmi.org.

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Doubting a diagnosis of dementia

A brilliant article by Kate Swaffer and a must read. I have been saying this over and over again, having worked in imaging for a short while. MRI and procedures for scans are stressful and distressing. And the whole process of diagnosis is just a mind field for everyone.

In the last few weeks, there have been a few articles, blogs or tweets on the impact of others publicly doubting a persons diagnosis of dementia, which I am highlighting here for your weekend reading! One tweet by a professional last week claimed with certainty some people don’t have dementia. Whilst it didn’t name anyone, it was disturbing. I’m reasonably certain, in the same way people rally around someone diagnosed with cancer, they also never doubt the diagnosis, including when the person ‘does better than expected‘.

People with cancer (or any other ‘mostly invisible’ diseases) are never diagnosed or doubted publicly, including by others after a conversation, presentation or after reading a book or blog. I can never tell who in a room has heart disease, diabetes, and in the early stages of conditions such as multiple sclerosis, and even Parkinson’s. It is the same for people with dementia as…

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Beastie Boy John Berry died of frontal lobe dementia – but what is it?

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Jan Oyebode, University of Bradford

John Berry, a founder member of the Beastie Boys, has died of dementia at the age of 52. Berry’s father told Rolling Stone magazine that his son died from frontal lobe dementia, a rare form of dementia more properly referred to as fronto-temporal dementia.

Symptoms of fronto-temporal dementia usually begin in late middle age. Because the disease is not very well known, people with fronto-temporal dementia often have delays in receiving a diagnosis and may find the services they need are not available.

A tricky term

The terms used for this dementia are confusing. The changes in the brain are referred to as “fronto-temporal lobar degeneration”. These do not initially have any effect on people’s behaviour. Once signs and symptoms show up, it is possible to diagnose the condition as one of the “fronto-temporal dementias”.

When the frontal lobes – the parts of the brain lying immediately behind the forehead – are mainly affected, there are changes in behaviour or personality, resulting in “behavioural variant fronto-temporal dementia”. When the temporal lobes – parts of the brain near the temples – are mainly affected, dementia shows up through changes in language, of which there are two types: semantic dementia and progressive non-fluent aphasia. Whichever type of fronto-temporal dementia people have, they do not come to the doctor complaining of the sort of problems with memory loss that most of us think of as being signs of dementia.

We don’t know the specific symptoms that John Berry had as each case of fronto-temporal dementia is different, but about four to 15 people in every 100,000 have fronto-temporal dementias – and there are some common symptoms.

Losing the supervisor

There is huge variation in how fronto-temporal dementia progresses. But over time, it usually affects more and more aspects of thinking and functioning. It is a condition that shortens life, with people living about three to ten years after diagnosis.

So what happens during the earlier stages of behavioural variant fronto-temporal dementia – the type that is sited in the frontal lobes? One way of thinking of this area of the brain is to imagine it as the supervisor of complex activities and social behaviour. When the supervisor starts to do its job poorly, people develop trouble with complicated tasks. They may not be able to get started, so they may seem apathetic and lacking in energy. When they get started they may get stuck in a groove.

Fronto-temporal dementia is sometimes confused with depression.
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One carer we spoke with described how his brother would drive the car late into the night until it ran out of petrol even though he knew, on one level, that he ought to stop to fill up.

Sometimes people repeat an action over and over in exactly the same way, perhaps arranging objects very precisely or following a set daily routine according to a strict timetable. As the frontal lobe overseer loosens control, people often become uninhibited. They may become blunt and tactless. They may act on appetites and urges in ways that are quite out of character: touching people, swearing profusely when irritated and eating excessive amounts of sweet foods.

A particular difficulty for friends and family is that people with this dementia lose their ability to empathise. They may no longer offer comfort if someone is in tears and may seem very self-centred.

As not many people are familiar with the condition, it is often mistaken for other more common conditions. People may put the changes down to mid-life crisis, stress at work, depression or the menopause. It is possible that the condition is often misdiagnosed.

On average, it takes four years to diagnosis after symptom onset for younger people with dementia, twice as long as for those over 65 years of age, by which time, relationships may have broken down. People with fronto-temporal dementia are often at a stage of life where they still have children – and sometimes parents – who depend on them. So this, coupled with their increasing needs for support can be very stressful for everyone. Yet a recent national survey, currently in press, found there was a lack of provision of appropriate care across most of the country.

Biomedical research is making strides in identifying many of the proteins that accumulate as plaques in the brains of the people affected. The genetic aspects which affect about one in every five to ten cases are also now understood. However, with a cure still a long way off, research into how to support and assist people to manage their day-to-day lives is also very important. In our research we have taken detailed accounts of the experiences of those affected and we will be using these to develop and test ways of helping people and their families to manage and live better with the condition.The Conversation

Jan Oyebode, Professor of Dementia Care, University of Bradford

This article was originally published on The Conversation. Read the original article.

Frontal lobe paradox: where people have brain damage but don’t know it

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Sam Gilbert, UCL and Melanie George, Canterbury Christ Church University

Humans have big brains and our frontal lobes, just behind the forehead, are particularly huge. Injuries to this part of the brain often happen after blows to the head or a stroke. Paradoxically, some people with frontal lobe injuries can seem unaffected – until they’ve been carefully evaluated.

The frontal lobes are sometimes described as the executives of the brain, or conductors of the orchestra. Among other things, they control and organise our thinking and decision-making processes. You rely on your frontal lobes when you do things like make plans, switch from one activity to another, or resist temptation.

Some people with frontal lobe injuries seem completely normal in short one-to-one conversations, but they actually have great difficulty with everyday tasks, such as cooking, organising their paperwork or remembering to take medication. This is called the frontal lobe paradox because, even though these people seem unimpaired when assessed, they have significant difficulties in everyday life.

Without specialist expertise in acquired brain injuries, it can be almost impossible to spot frontal lobe paradox because, in many cases, people will still be able to speak normally and seem remarkably unimpaired. They may be unaware of their difficulties and deny that they need any help or support.

Insight issues

People affected by the condition are not lying when they say they don’t need help or support. Instead, they may lack knowledge of their own condition because areas of the frontal lobes that are responsible for self-monitoring and developing insight have been affected by their brain damage.

A second reason for the frontal lobe paradox is that the skills needed for an assessment interview are different from those needed in everyday life. The structure and routine of an environment, such as a rehabilitation ward, can, in effect, play the role of someone’s frontal lobes. This can mask the difficulties people experience in less structured, open-ended environments. For this reason, a person’s level of ability needs to be assessed in a situation that resembles everyday life. A seemingly simple task, such as going shopping, can reveal difficulties in people who appear unimpaired on standard tests of memory and attention, and have normal intelligence.

People with frontal lobe paradox may need help with things like cooking.
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Lack of specialist training

Neuroscientists and doctors have known about the frontal lobe paradox for at least 50 years, but it is not always understood by non-specialists. This situation can lead to people not receiving help they desperately need.

For example, in England and Wales, social workers and care managers are usually responsible for deciding whether a person has the capacity (under the Mental Capacity Act 2005) to decline support or care. These are hardworking professionals who are motivated to act in the best interests of those under their care, but many receive little or no specialist training in brain injury.

These professionals tend to base their decision about a person’s mental capacity on a short face-to-face interview. This is exactly the situation that can lead to people with frontal lobe damage being denied the care that they need.

The assessment provides the support needed for a person to sound competent and able, but only for the duration of the assessment. In one example, a woman persuaded a series of professionals that she could safely live alone after a significant brain injury. In reality, she could not make meals for herself or remember to take her lifesaving medication. Sadly, she died at home shortly afterwards.

Support needed

We don’t know exactly how common the condition is, but the frontal lobe paradox is probably found in a much higher number of people than you might first imagine. As well as those who have suffered blows to the head and strokes, it can affect people with certain infections, some forms of dementia and even poorly controlled diabetes.

It is vital that social workers and care managers are trained on brain injury to protect the interests of people with frontal lobe injuries. People with these injuries are in particular need of support, but they are often the least likely to receive it.The Conversation

Sam Gilbert, Associate Professor, Institute of Cognitive Neuroscience, UCL and Melanie George, Consultant Clinical Neuropsychologist, Canterbury Christ Church University

This article was originally published on The Conversation. Read the original article.

Is there really a benefit from getting an early dementia diagnosis?

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Tim Gomersall, University of Huddersfield

The Alzheimer’s Society recently issued a call for people with symptoms such as memory loss and confusion to seek early medical help. The British charity is worried that people may be putting off getting a dementia diagnosis and not receiving the health care and support they need. As the Alzheimer’s Society’s recent blog post put it: “A lack of diagnosis is denying many people with dementia the chance of getting the best possible treatment, information and support – evidence shows the earlier on you receive these, the better your chance of living well for longer.” But is early diagnosis always a good thing?

Early diagnosis has also been a key policy aim for government. We can see this in the National Dementia Strategy, and David Cameron’s Challenge on Dementia. A few years ago, the NHS even trialled a scheme to pay GPs £55 for each dementia diagnosis made. This move was widely condemned by doctors’ groups and quietly dropped after six months. In any event, the push for earlier diagnosis continues. So what exactly are the benefits of earlier diagnosis? And who are the beneficiaries?

What works?

There are no known treatments to prevent or reverse dementia, although drugs called memantine and acetylcholinesterase inhibitors can help to relieve symptoms .

In the course of my recent fieldwork, however, I met some people with memory loss who invested hope in these treatments beyond what was possible. They believed that getting onto anticholinesterase inhibitors as soon as possible could delay further decline.

Drugs can help with symptoms.
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One of the most difficult experiences in my recent research was meeting a woman who felt she had been denied treatment by the doctors, and asked me and my colleague if we were able to prescribe them for her. We had to explain that we were not clinically qualified, and in any case, the drugs would not prevent the progression of dementia. But false hope can translate into big profits for drugs companies.

The anticholinesterase inhibitor market had an estimated value of US$4.2 billion globally in 2011, with this figure set to increase over coming years as people live longer. One recent market analysis identified early diagnosis as “a challenge [that] will affect the growth of the market over the 2013-2023 forecast period”.

Thankfully, drug treatment is not the only option for people with dementia. Anyone with suspected dementia can access a memory clinic on the NHS to seek practical support for their needs. Memory clinics typically include a range of health professionals – including occupational therapists, psychologists, specialist nurses and psychiatrists. These multidisciplinary teams can help with emotional and occupational support. They can also offer advice on adapting homes – for instance, by providing memory aids, grab rails for bathing and toileting, and extra lighting.

The National Institute for Health and Care Excellence (NICE) also recommends “group cognitive stimulation programmes”. Cognitive stimulation uses enjoyable activities to engage thinking and memory – for example, musical activities, reminiscence sessions, and games. A recent review suggests this approach could help to maintain cognitive abilities, particularly memory and communication.

However, the current evidence relies on a number of small trials of often quite different activities, going back to 1979. Nevertheless, in the absence of effective drug treatments, cognitive stimulation is important for many people with dementia, and continues to attract research and practice interest.

Finally, we shouldn’t underestimate the psychological importance of receiving a diagnosis. Overall, the evidence shows a mixed picture. On the one hand, people are glad to understand the cause of their symptoms, to be able to plan for the future, and access resources such as dementia support groups. However, people often worry about the stigma of dementia, and some want to avoid the emotional impact of the diagnosis.

Is earlier better?

Over the last couple of years, I’ve been involved in a project looking at people’s experiences of mild cognitive impairment. This syndrome is defined as a “boundary state” between cognitive ageing (a normal process) and dementia.

If the Alzheimer’s Society’s suggestion that dementia is being under-diagnosed holds, then people with mild cognitive impairment are an anomaly. They have sought medical advice for possible dementia symptoms which are not severe enough for a diagnosis. Might it be that more people are already seeking help earlier, as the Alzheimer’s Society hopes? It seems plausible.

After the National Dementia Strategy was launched, there was a 12% increase in dementia diagnosis rates in the UK between 2009 and 2011, and recent studies show a continued upward trend.

So, who benefits from early diagnosis? As suggested above, a number of commercial and charitable organisations stand to gain substantially. There are also some benefits that may accrue to people with dementia from an early diagnosis in terms of symptom control and cognitive stimulation. Though any potential gains are small, these can still be meaningful to the person.

The other side of this, however, is the risk of over-diagnosis and increased public health anxiety associated with such “public awareness” campaigns. For example, our recent review of mild cognitive impairment research suggests people with this diagnosis live with significant uncertainty about the cause of their problems.

These patients often continue to worry about possible dementia, and the infrastructure for supporting them is patchy at best. The ethics of diagnosing people who may have no underlying illness has also been questioned. So yes, we should be helping people with dementia to get the support they need as soon as possible. But this shouldn’t come at the cost of over-diagnosing and over-medicating people.The Conversation

Tim Gomersall, Senior Lecturer in Psychology, University of Huddersfield

This article was originally published on The Conversation. Read the original article.