Easing family distress: New international guidelines to identify dementia with L

June 7, 2017

New guidelines have been published on the clinical and physical indicators to help ensure patients with dementia with Lewy bodies get an accurate diagnosis and the best care possible.

The death of Hollywood actor Robin Williams in 2014 threw the condition into the spotlight as it was identified he struggled with the illness.

Now scientists at Newcastle University, UK, have led an international team of experts to produce new recommendations to help diagnose the disease more accurately and improve management of the complex disorder.

According to research published online today and in the July 4, 2017, issue of Neurology, the medical journal of the American Academy of Neurology, the world leaders in their field highlight important clinical and diagnostic biomarkers, but call for more clinical trials into the illness.

Ian McKeith, Professor of Old Age Psychiatry at Newcastle University's Institute for Ageing, led the international dementia with Lewy bodies (DLB) consortium, which last reported on diagnosis and management of the illness in December 2005.

Professor McKeith has been instrumental in leading this research over the past decade, which has been supported by the NIHR Newcastle Biomedical Research Centre, a partnership between Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University.

The new recommendations were established by experts, including patients and care organisations and highlight the importance of detecting the disease early.

Professor McKeith said: "There remains a pressing need to understand DLB, to develop and deliver clinical trials, and to help patients and carers worldwide inform themselves about their disease.

"It is important that people are aware of the condition's prognosis, best available treatments, ongoing research, and how to get adequate support.

"Our guidelines now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about the best methods to establish and interpret these.

"Without accurate diagnosis we can't do the clinical trials that are needed to demonstrate a treatment that works."

DLB is a disorder that shares symptoms with both Alzheimer's disease and Parkinson's disease. It may account for 10% to 15% of all cases of dementia yet it is not sufficiently recognised.

The new guidelines focus on clinical features, such as visual hallucinations, motor features of Parkinson's disease, and rapid eye movement sleep behaviour disorder.

Detailed information is also provided about the best biomarkers to use to help confirm a diagnosis when a patient presents with one or more clinical features.

It is estimated that more than 100,000 people in the UK are affected by the illness, and over 5 million people worldwide.

Professor McKeith said: "Newcastle has been at the forefront of DLB research since the late 1980s and we continue to be so as more and more is understood about the condition."

Future research will focus on family studies to find genes relating to DLB, on collecting biological samples from large population-based cohorts, and on developing a publicly available DLB genetic database.

Jacqui Cannon, CEO of the Lewy Body Society, said: "It is so important that people receive a diagnosis of the correct subtype of dementia, only then will they receive the correct support, care and medication. This is particularly important for people living with DLB."

Case study

Debbie Ainscow knows first-hand the devastation that dementia with Lewy bodies can cause as her father lived with the condition for more than seven years before his death, aged just 79.

Harry lived an active lifestyle, yet his illness turned him into a man who was unrecognisable as he suffered upsetting visual hallucinations, became incoherent at times, and was rigid in his movements.

Mother-of-one Debbie, 48, of Boldon, South Tyneside, said: "I didn't know anything about the condition until my dad received his diagnosis - it came as a shock and was devastating.

"It was heartbreaking to see how the condition changed him. He would shuffle along and became very rigid in the way that he would walk and move.

"It was very upsetting and challenging to see my dad's dramatic change in personality and his aggressive behaviour, this was probably the hardest part.

"At the time we didn't know anything about DLB and it was difficult, especially for my mum, Marjorie, who was with him 24/7.

"Had we had the ability to access guidelines like the ones published today it would have made a big difference and we would have felt less stressed because we'd have understood the condition better.

"It is very important that patients and families know how the illness presents itself as this can help people develop coping strategies to get the best quality of life possible.

"It is fantastic that Newcastle is leading the research into DLB and I am delighted to see that new recommendations of how to diagnose and manage the condition have been published."

More information: Neurology (2017). DOI: 10.1212/WNL.0000000000004058

Journal reference: Neurology

Provided by: Newcastle University

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New mechanism behind Parkinson's disease revealed

June 5, 2017

An illustration of the alpha-synuclein protein. Credit: RCSB Protein Data Bank

Parkinson's disease is a debilitating neurological illness that affects approximately 10 million people worldwide. It is marked by a progressive decline in physical function, the most iconic being uncontrollable tremors, and involves the malfunction and eventual death of nerve cells located in the brain. There is no cure for this disease, and researchers have struggled for years to fully understand its cause. In the 1990s, the field of Parkinson's research took a great leap forward when an overabundance of the protein alpha-synuclein was linked to disease development. This protein, a mysterious inhabitant of the brain, is found mainly at the end of neurons in what is called the nerve terminal. Attempts to precisely identify its role in Parkinson's since the link was discovered have been unsuccessful, until now.

Researchers at the Okinawa Institute of Science and Technology Graduate University (OIST) have found that the protein hinders a key step involved in the transmission of neuronal signals, which is essential for higher-brain functioning: vesicle endocytosis at the nerve terminal. The study has been accepted for early release in the Journal of Neuroscience.

Neurotransmission is a process that allows neurons to pass signals between one another—signals important for motor, sensory, and cognitive functioning. When an electrical signal arrives at a nerve terminal and needs to be passed along to the next neuron, neurotransmitters, or chemical messengers, packed in vesicles mediate this process. A vesicle is a container made of a lipid membrane from which a neurotransmitter is released into the synaptic cleft—the space between neurons. After being released, the neurotransmitter is caught by receptors in an adjacent neuron and the signal is passed along for further transmission. Meanwhile, the empty vesicle is recycled back into the nerve terminal to be used again.

The retrieval of an emptied vesicle membrane is called "endocytosis," and it is this process that an overabundance of alpha-synuclein disrupts. Endocytosis is critical for proper neurotransmission—when it is inhibited, the rest of the steps involved in transmission are affected as well.

"If you inhibit [endocytosis in the nerve terminal], then the vesicle recycling becomes slower and the supply of the vesicles is inhibited," OIST Professor Tomoyuki Takahashi from the Cellular and Molecular Synaptic Function Unit explains. "If you are using the vesicles mildly, this is okay, but if you start to use them heavily, then it becomes a problem."

The vesicles are represented by blue and white circles at the top left. The white circles are empty and the blue ones contain a neurotransmitter. "Full" vesicles move toward the membrane of the nerve terminal, represented by the overall outline of the figure, where they attach and fuse into the terminal membrane, thereby releasing the transmitter into the space between neurons, the synaptic cleft. This release is illustrated by a blue omega-shaped structure at the bottom of the terminal membrane. When a vesicle becomes "empty," the vesicle membrane is retrieved into the terminal -- white circles on the right -- and then recycled back to the release sites, which are illustrated as red bars. Credit: Okinawa Institute of Science and Technology Graduate University (OIST)

High-frequency transmission, in which vesicles are heavily used, is important for processes such as sensory perception, generating memories, and motor control. The OIST researchers found that when endocytosis is inhibited, high-frequency transmission breaks down much more quickly than it would under normal circumstances.

A deeper look into the mechanism by which alpha-synuclein inhibits endocytosis revealed toxic effects of the over-assembly of microtubules.

"Microtubule is a structure protein," Professor Takahashi explains. "It's like a pillar of a house." Apparently, too much alpha-synuclein in the nerve terminal causes microtubules to over-assemble and somehow get in the way of endocytosis. It is like having too many pillars in a house and in all the wrong places—one could imagine such a house would be difficult to live in and navigate properly.

Researchers believe that this inhibitory process caused by an overabundance of alpha-synuclein is what occurs in the early stages of Parkinson's disease, before morphological changes such as the loss of function and death of neurons begins.

When asked whether these results can help aid in developing treatment for Parkinson's disease, Professor Takahashi replies: "I think we are getting close. We know the initial target and the mechanism...[But] in order to step into [the treatment] stage, we should probably work a little bit more to know by what mechanism the microtubules interfere with endocytosis."

More information: Kohgaku Eguchi et al, Wild-type monomeric α-synuclein can impair vesicle endocytosis and synaptic fidelity via tubulin polymerization at the calyx of Held, The Journal of Neuroscience (2017).  DOI: 10.1523/JNEUROSCI.0179-17.2017 

Journal reference: Journal of Neuroscience

 Provided by: Okinawa Institute of Science and Technology

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Potential therapeutic target for Parkinson's disease

June 7, 2017

Credit: Juntendo University

Investigations by scientists in Japan illustrate how the loss of a key mitochondrial protein facilitates the progression of Parkinson's disease. The findings are published in Nature Communications (June 2017).

There is much evidence to suggest that dysfunction within cellular components contributes to the development and progression of the neurodegenerative disorder Parkinson's disease. However, exactly how individual genes and proteins contribute to the degradation of this integral cellular structure is unclear.

Mitochondria are sub-units within cells that control biochemical processes such as energy production. They have a double-membrane structure, the inner membrane of which forms multiple layers or 'cristae.' Each crista structure must remain intact in order for the mitochondria to perform their tasks effectively.

Now, Hongrui Meng and Chikara Yamashita at Juntendo University Graduate School of Medicine in Tokyo, and co-workers across Japan, have shown how a mitochondrial protein called CHCHD2 plays a key role in maintaining cristae structure and mitochondria integrity.

Meng and Yamashita's team generated CHCHD2 mutant fruit flies (Drosophila), and examined what happened when CHCHD2 protein expression was lost. They found that this loss resulted in abnormal matrix structures and impairments to oxygen respiration in mitochondria. This in turn led to neuron loss through oxidative stress, and also to motor dysfunction – such as loss of climbing ability—as the flies aged.

When the researchers introduced a wild-type form of human CHCHD2 and a metabolic regulator 4E-BP to the flies, the dysfunctions were reversed. Further investigations showed that CHCHD2 binds to a mitochondrial protein cytochrome c along with a cell death regulator MICS-1. This binding helps cells to function properly and ensure correct cell death signaling in both mammalian cells and Drosophila. 

As the team states in their paper published in Nature Communications, their results shed light on the role of CHCHD2 mutations in Parkinson's disease and offer "potential therapeutic targets in Parkinson's caused by mitochondrial dysfunction."

Background

The recent discovery of a gene related to Parkinson's disease, CHCHD2, is allowing scientists to directly investigate the molecular details behind the disorder in more depth. The gene encodes a protein, CHCHD2, the role of which Hongrui Meng and his team in Japan aimed to investigate using fruit fly and mouse models.

The mutant fruit flies lacked the CHCHD2 protein, resulting in flies with shorter life spans and problems with motor function as they aged. The loss of the protein resulted in the integral structure of the flies' mitochondria was disrupted. The researchers also discovered that by affecting the oxygen respiration processes within mitochondria, the loss of CHCHD2 generates excess reactive oxygen species in the body. This in turn exacerbates oxidative stress and directly affects the function and survival of neurons in the body. Importantly, these phenotypes were not rescued by the reintroduction of CHCHD2 missense mutants associated with Parkinson's disease, strongly suggesting that this disease develops by the loss of CHCHD2 function. 

Implications of the current study

These findings suggest that CHCHD2 is a key protein that regulates the mitochondrial respiratory function through stabilizing cytochrome c. Without it, through mutations in the CHCHD2 gene, mitochondria cannot function correctly, leading to the progression of Parkinson's disease. The researchers believe their insights into the gene, its associated protein, and how the protein works to facilitate healthy functioning of mitochondria could inform future therapies for Parkinson's disease and help scientists better understand the condition.

More information: Loss of Parkinson's disease-associated protein CHCHD2 affects crista structure and destabilizes cytochrome c. Nature Communications DOI: 10.1038/ncomms15500 

Journal reference: Nature Communications

Provided by: Juntendo University

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