Posts Tagged ‘neurodegeneration’


Prof Sarah Tabrizi , from the UCL Institute of Neurology, led the trials

By James Gallagher

The defect that causes the neurodegenerative disease Huntington’s has been corrected in patients for the first time, the BBC has learned. An experimental drug, injected into spinal fluid, safely lowered levels of toxic proteins in the brain. The research team, at University College London, say there is now hope the deadly disease can be stopped.

Experts say it could be the biggest breakthrough in neurodegenerative diseases for 50 years.

Huntington’s is one of the most devastating diseases. Some patients described it as Parkinson’s, Alzheimer’s and motor neurone disease rolled into one.

Peter Allen, 51, is in the early stages of Huntington’s and took part in the trial: “You end up in almost a vegetative state, it’s a horrible end.”

Huntington’s blights families. Peter has seen his mum Stephanie, uncle Keith and grandmother Olive die from it. Tests show his sister Sandy and brother Frank will develop the disease. The three siblings have eight children – all young adults, each of whom has a 50-50 chance of developing the disease.

The unstoppable death of brain cells in Huntington’s leaves patients in permanent decline, affecting their movement, behaviour, memory and ability to think clearly.

Peter, from Essex, told me: “It’s so difficult to have that degenerative thing in you.

“You know the last day was better than the next one’s going to be.”
Huntington’s generally affects people in their prime – in their 30s and 40s
Patients die around 10 to 20 years after symptoms start
About 8,500 people in the UK have Huntington’s and a further 25,000 will develop it when they are older

Huntington’s is caused by an error in a section of DNA called the huntingtin gene. Normally this contains the instructions for making a protein, called huntingtin, which is vital for brain development. But a genetic error corrupts the protein and turns it into a killer of brain cells.

The treatment is designed to silence the gene.

On the trial, 46 patients had the drug injected into the fluid that bathes the brain and spinal cord. The procedure was carried out at the Leonard Wolfson Experimental Neurology Centre at the National Hospital for Neurology and Neurosurgery in London. Doctors did not know what would happen. One fear was the injections could have caused fatal meningitis. But the first in-human trial showed the drug was safe, well tolerated by patients and crucially reduced the levels of huntingtin in the brain.

Prof Sarah Tabrizi, the lead researcher and director of the Huntington’s Disease Centre at UCL, told the BBC: “I’ve been seeing patients in clinic for nearly 20 years, I’ve seen many of my patients over that time die. For the first time we have the potential, we have the hope, of a therapy that one day may slow or prevent Huntington’s disease . This is of groundbreaking importance for patients and families.”

Doctors are not calling this a cure. They still need vital long-term data to show whether lowering levels of huntingtin will change the course of the disease. The animal research suggests it would. Some motor function even recovered in those experiments.

Peter, Sandy and Frank – as well as their partners Annie, Dermot and Hayley – have always promised their children they will not need to worry about Huntington’s as there will be a treatment in time for them. Peter told the BBC: “I’m the luckiest person in the world to be sitting here on the verge of having that. “Hopefully that will be made available to everybody, to my brothers and sisters and fundamentally my children.”

He, along with the other trial participants, can continue taking the drug as part of the next wave of trials. They will set out to show whether the disease can be slowed, and ultimately prevented, by treating Huntington’s disease carriers before they develop any symptoms.

Prof John Hardy, who was awarded the Breakthrough Prize for his work on Alzheimer’s, told the BBC: “I really think this is, potentially, the biggest breakthrough in neurodegenerative disease in the past 50 years. That sounds like hyperbole – in a year I might be embarrassed by saying that – but that’s how I feel at the moment.”

The UCL scientist, who was not involved in the research, says the same approach might be possible in other neurodegenerative diseases that feature the build-up of toxic proteins in the brain. The protein synuclein is implicated in Parkinson’s while amyloid and tau seem to have a role in dementias.

Off the back of this research, trials are planned using gene-silencing to lower the levels of tau.

Prof Giovanna Mallucci, who discovered the first chemical to prevent the death of brain tissue in any neurodegenerative disease, said the trial was a “tremendous step forward” for patients and there was now “real room for optimism”.

But Prof Mallucci, who is the associate director of UK Dementia Research Institute at the University of Cambridge, cautioned it was still a big leap to expect gene-silencing to work in other neurodegenerative diseases.

She told the BBC: “The case for these is not as clear-cut as for Huntington’s disease, they are more complex and less well understood. But the principle that a gene, any gene affecting disease progression and susceptibility, can be safely modified in this way in humans is very exciting and builds momentum and confidence in pursuing these avenues for potential treatments.”

The full details of the trial will be presented to scientists and published next year.

The therapy was developed by Ionis Pharmaceuticals, which said the drug had “substantially exceeded” expectations, and the licence has now been sold to Roche.

http://www.bbc.com/news/health-42308341

Advertisements

Last year, doctors of optometry detected more than 320,000 cases of diabetes. Imagine if they could make the same impact when it comes to exposing early signs of Alzheimer’s disease.

November is National Alzheimer’s Disease Awareness Month. An estimated 5.4 million Americans are affected by Alzheimer’s disease, according to the Centers for Disease Control and Prevention (CDC). Projections put the number at 13.8 million by 2050.

Maryke Nijhuis Neiberg, O.D., associate professor in the School of Optometry at Massachusetts College of Pharmacy and Heath Sciences, in Worcester, Massachusetts, considers this an unrealized patient education opportunity for doctors of optometry.

“The earlier diagnoses give doctors and patients a better chance at managing the progressive brain disease and preserving the patient’s quality of life,” Dr. Neiberg says. “There has been some increase in Alzheimer’s awareness over the years, particularly in the eye community, but not enough yet.

“Alzheimer’s is a significant future public health issue,” she adds. “It is still a terminal disease.”

Early intervention

Much of the research on Alzheimer’s disease seeks to slow the disease’s progression. For instance, a study in Biological Psychiatry on Nov. 6 by researchers at the University of Iowa and the University of Texas Southwestern Medical Center in Dallas reports that there may be a new treatment that can slow the depression and cognitive decline associated with Alzheimer’s disease, without affecting amyloid plaque deposits or reactive glia in rats.

Among the early signs of Alzheimer’s, the researchers say, are anxiety, depression and irritability-long before the devastating effects of memory loss.

“Thus, P7C3 compounds may form the basis for a new class of neuroprotective drugs for mitigating the symptoms in patients with Alzheimer’s disease by preserving neuronal cell survival, irrespective of other pathological events,” researchers say. “P7C3 compounds represent a novel route to treating depression, and new-onset depression in elderly patients may herald the development of Alzheimer’s disease with later cognitive impairments to follow.”

Another study in JAMA Ophthalmology in September by researchers at Stanford University and Veterans Affairs Palo Alto Health Care System linked visual impairment and cognition in older adults and also stressed the “potential importance” of vision screening in identifying these patients’ eye disease and cognitive deficits. The AOA strongly recommends comprehensive eye examinations and stresses the limitations of screenings.

Optometry’s role

According to the CDC:

The rate of Alzheimer’s jumped 50 percent between 1999 and 2014.

Americans fear losing their mental capacity more than losing their physical abilities.

More than $230 billion is estimated to be spent in 2017 on providing health care, long-term care, hospice plus unpaid care for relatives with Alzheimer’s and other dementias.

More large-scale research on Alzheimer’s needs to be done, but progress is being made. Dr. Neiberg pointed to research linking optical coherence tomography (OCT) of the macula to Alzheimer’s and Parkinson’s diseases.

“With the advent of OCT, we now know that the retinal ganglion cell layer thins and that the optic nerve cup-to-disc ratio increases in size, not unlike glaucoma,” Dr. Neiberg says. “Alzheimer’s produces visual field defects that are easily confused with glaucoma. What we need is large-scale research to determine how much of the normal tension glaucoma we diagnose and treat is ultimately related to Alzheimer’s disease.”

She adds, “The early perceptual changes that occur in early Alzheimer’s are startling and measurable. One of the earliest signs is a decline in the Benton Visual Retention Test, a test of visual memory. This test requires the duplication of shapes on paper with a pencil, and is scored.

“Research has shown that this test is able to predict high risk for Alzheimer’s 15 years before diagnosis,” she says. “It’s a simple test many developmental and pediatric optometrists already have on their shelves. If we combine that test and the ocular findings we see, we have a very strong indication that something is indeed amiss. Armed with this information, the patient can then consult with their primary care physician, initiate lifestyle modification and request a referral if necessary.”

There is no cure for Alzheimer’s disease. But doctors of optometry can engage patients in conversation about Alzheimer’s disease and how they can manage their own risk factors, including:

Smoking
Mid-life obesity
Sedentary lifestyle
High-cholesterol diet|
Vascular disease (i.e., diabetes and hypertension)

“Lifestyle modification and early access to medication, which can delay the progression of dementia, might be enough to keep the disease at bay for longer,” Dr. Neiberg says. “We should include the Alzheimer’s disease connection when we educate our patients about lifestyle diseases.”

https://finchannel.com/society/health-beauty/69483-doctors-of-optometry-can-spot-early-signs-of-alzheimer-s-disease

by CHRIS SMYTH

People living in areas with high levels of lithium in tap water are 17 per cent less likely to get dementia, according to a large study that suggests the naturally occurring metal could help to prevent mental decline.

The findings raise the possibility that lithium could one day be added to drinking water to protect the brain in the same way as fluoride is added to protect teeth.

Lithium is already widely available as a psychiatric drug and experts said the findings suggested that it could be used as a treatment to prevent dementia if further trials proved successful. Lithium is known to affect neurological signalling and has long been used as a treatment for conditions such as bipolar disorder. It occurs naturally in water and previous studies have found lower suicide rates in areas with higher levels.

Scientists studied 74,000 older people with dementia and 734,000 without across Denmark, comparing illness rates with lithium levels, which were 15 times higher in some areas.

Scientists at the University of Copenhagen found that dementia rates increased slightly with low levels of lithium before falling sharply above 10 micrograms per litre. At 15 to 27 micrograms/l, dementia rates were 17 per cent lower than for 2-5 micrograms/l, according to results published in JAMA Psychiatry.

The authors acknowledged that other factors could explain the results, including worse healthcare in the remoter areas that had less lithium in water, but they said it was plausible that tiny amounts in tap water could have a significant effect on dementia.

In a linked editorial John McGrath, of the University of Queensland, and Michael Berk, of the University of Melbourne, wrote: “In the spirit of alchemy, could we convert lithium, a simple metal used as a mood stabiliser, into a golden public health intervention that could prevent dementia?

They added: “That a relatively safe, simple, and cheap intervention (ie optimising lithium concentrations in the drinking water) could lead to the primary prevention of dementia is a tantalising prospect.”

David Smith, emeritus professor of pharmacology at the University of Oxford, said the findings tallied with MRI studies showing that lithium salts increased the volume of areas of the brain involved in Alzheimer’s. However, he added: “We should not be adding lithium salts to our tap water because we would not know what amount to use.”

David Reynolds, chief scientific officer at Alzheimer’s Research UK, said: “It is potentially exciting that low doses of a drug already available in the clinic could help limit the number of people who develop dementia.”

Rob Howard, professor of old-age psychiatry at University College London, said: “These results represent another important piece of evidence for lithium’s potential as a treatment for Alzheimer’s disease. We now need clinical trials of lithium in patients with Alzheimer’s disease to determine once and for all whether this cheap and well-tolerated element can slow dementia progression.”

http://www.theaustralian.com.au/news/world/the-times/lithium-in-tap-water-could-lower-dementia-risk/news-story/c40599203eca195402c03c0a168961a6


A key metabolic pathway must be switched off during neuron development or fewer neurons (green, on the right) survive.

by Jennifer Hicks

Researchers at the Salk Institute of Biological Studies released a study in the July 12 issue of eLife, which identifies the point at which there’s a dramatic metabolic shift in developing neurons. This discovery of the path a neuron takes during development could help provide insight into neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.

In a press release, Tony Hunter, American Cancer Society Professor, Salk Molecular and Cell Biology Laboratory said there’s relatively little understanding about how neuron metabolism is first established.

Oxidative stress leads to disruptions in neural cells which are key players in neurodegenerative diseases like Parkinson’s or ALS. The brain needs oxygen to survive but by knowing when and how neuron metabolism goes off track and mitochondria fail to function properly in these diseases, researchers can begin to devise ways to re-route metabolic processes to prevent degeneration.

“Aside from enabling us to understand this process during neuronal development, the work also allows us to better understand neurodegenerative disease,” added Hunter.

What the researchers found in the study was that while neurons shut off the aerobic glycolysis to survive during the metabolic process at the same time neurons also had to kick-start oxidative phosphorylation in order to survive. When the researchers stopped that metabolic process from happening, the neurons died. A neuron dysfunction of any kind can potentially lead to neurodegenerative disease for a number of reasons.

http://www.forbes.com/sites/jenniferhicks/2016/07/31/a-look-at-the-metabolic-shift-in-neurons-for-insight-into-neurodegenerative-disease/#14296174e07b

By Patrick Foster

Lawyers, teachers and doctors have a better chance of fighting off the effects of Alzheimer’s disease, because of the complex nature of their jobs, scientists reported this week.

Researchers found that people whose jobs combined complex thinking with social engagement with others – such as social workers and engineers – were better protected against the onset of Alzheimer’s, compared to those in manual work.

The study came as another report suggested that people with a poor diet could protect themselves against cognitive decline by adopting a mentally stimulating lifestyle.

Both pieces of research, published at the international conference of the Alzheimer’s Association, in Toronto, examined the impact of complex thinking on the onset of the disease.

In the first study, carried out by scientists at the Alzheimer’s Disease Research Centre, in Wisconsin, researchers examined white matter hyperintensities (WMHs) – white spots that appear on brain scans and are associated with Alzheimer’s – in 284 late-middle-aged patients considered at risk of contracting the disease.

They found that people who worked primarily with other people, as opposed to with “things or data”, were less likely to be affected by brain damage indicated by WMHs.

While lawyers, social workers, teachers and doctors were best protected, those who enjoyed the least protection included shelf-stackers, machine operators and labourers.

Elizabeth Boots, a researcher on the project, said: “These findings indicate that participants with higher occupational complexity are able to withstand pathology associated with Alzheimer’s and cerebrovascular disease and perform at a similar cognitive level as their peers.

“This association is primarily driven by work with people, rather than data or things. These analyses underscore the importance of social engagement in the work setting for building resilience to Alzheimer’s disease.”

The second study, carried out by Baycrest Health Sciences, in Toronto, examined the diet of 351 older adults.

Researchers found that those who had a traditional Western diet of red and processed meat, white bread, potatoes and sweets were more likely to experience cognitive decline.

However, those who adhered to such a diet but who had a mentally stimulating lifestyle enjoyed some protection from such decline.

Dr Matthew Parrott, one member of the team, said: “Our results show the role higher educational attainment, mentally stimulating work and social engagement can play in protecting your brain from cognitive decline, counteracting some negative effects of an unhealthy diet.

“This adds to the growing body of evidence showing how various lifestyle factors may combine to increase or protect against vulnerability to Alzheimer’s disease.”

Other research put forward at the convention included a study showing that digital brain training exercises can help stave of Alzheimer’s, and another paper that suggested that some newly-identified genes may also increase resilience to the disease.

Maria C. Carrillo, the chief science officer at the Alzheimer’s Association, said: “These new data add to a growing body of research that suggests more stimulating lifestyles, including more complex work environments with other people, are associated with better cognitive outcomes in later life.

“As each new study emerges, we further understand just how powerful cognitive reserve can be in protecting the brain from disease. Formal education and complex occupation could potentially do more than just slow cognitive decline – they may actually help compensate for the cognitive damage done by bad diet and small vessel disease in the brain.

“It is becoming increasingly clear that in addition to searching for pharmacological treatments, we need to address lifestyle factors to better treat and ultimately prevent Alzheimer’s and other dementias.”

http://www.telegraph.co.uk/news/2016/07/24/stressful-job-it-might-help-you-fight-off-alzheimers/

New findings indicate that phosphorylated LRRK2 (leucine-rich repeat kinase 2) protein levels in urine are elevated in patients diagnosed with idiopathic Parkinson Disease (PD), and that urinary phosphorylated LRRK2 levels correlate with the presence and severity of symptoms such as cognitive impairment in individuals with PD. Researchers affiliated with the University of Alabama at Birmingham published their findings in Neurology and in Movement Disorders (1,2).

The etiology of PD is currently unknown and mechanisms of action are still not completely clarified. It is well established, however, that aging is the single most important risk factor. PD is the second most frequent age-related neurodegenerative disorder, and one of the key pathogenic features is slow and progressive neuronal death that is concomitant with cognitive dysfunction. Current therapeutic modalities are inadequate and clinical need is significant. More than 6 million individuals worldwide are diagnosed with PD.

To date, several common genetic variants, or single nucleotide polymorphisms (SNPs), have been identified that influence the risk for disease. For example, polymorphic variants in LRRK2 gene have previously been validated as genetic factors that confer susceptibility to PD.

Although the gene remains poorly characterized, five different mutations in the gene encoding LRRK2 are considered a common cause of inherited PD (3). One of the five mutations that are causal is the G2019S mutation in the LRRK2 kinase domain, a mutation that significantly increases phosphorylation activity (1,3).

“There are currently no known ways to predict which G2019S mutation carriers will develop PD,” the authors wrote in the Neurology publication. Investigators purified LRRK2 protein from urinary exosomes collected from a total of 76 men. (Exosomes are membrane vesicles of endosomal origin that are secreted by most cells in culture, and are present in most biological fluids such as urine, blood, and saliva.) Then, they compared the ratio of phosphorylated LRRK2 to total LRRK2 in urine exosomes. Results show that “elevated … phosphorylated LRRK2 predicted the risk” for onset of PD in LRRK2 G2019S mutation carriers (1).

In their follow-up study, which was published in Movement Disorders, investigators compared phosphorylated LRRK2 levels in urine samples of 79 individuals diagnosed with PD to those of 79 healthy control participants. Results show that phosphorylated LRRK2 levels were significantly elevated in patients with PD when compared to those of controls. Also, phosphorylated LRRK2 levels correlated with the severity of cognitive impairment in patients with PD (2).

“Because few viable biomarkers for PD exist … phosphorylated LRRK2 levels may be a promising candidate for further exploration,” the authors concluded in their publication.

References
1. Fraser KB, Moehle MS, Alcalay RN, et al. Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers. Neurology. 2016;86:994-999.
2. Fraser KB, Rawlins AB, Clar RG, et al. Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson’s disease. Mov Disord. 2016. doi: 10.1002/mds.26686.
3. Greggio E, Cookson MR. Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: three questions. ASN Neuro. 2009;1:e00002.

http://www.psychiatryadvisor.com/neurocognitive-disorders/urinary-biomarker-of-parkinson-disease-identified/article/508195/?DCMP=EMC-PA_Update_RD&cpn=psych_md,psych_all&hmSubId=&hmEmail=5JIkN8Id_eWz7RlW__D9F5p_RUD7HzdI0&NID=1710903786&dl=0&spMailingID=14919209&spUserID=MTQ4MTYyNjcyNzk2S0&spJobID=820575619&spReportId=ODIwNTc1NjE5S0


Infection with the common parasite Toxoplasma gondii promotes accumulation of a neurotransmitter in the brain called glutamate, triggering neurodegenerative diseases in individuals predisposed to such conditions.

Written by Honor Whiteman

This is the finding of a new study conducted by researchers from the University of California-Riverside (UC-Riverside), recently published in PLOS Pathogens.

T. gondii is a single-celled parasite that can cause a disease known as toxoplasmosis.

Infection with the parasite most commonly occurs through eating undercooked, contaminated meat or drinking contaminated water.

It may also occur through accidentally swallowing the parasite after coming into contact with cat feces – by cleaning a litter tray, for example.

Though more than 60 million people in the United States are believed to be infected with T. gondii, few people become ill from it; a healthy immune system can normally stave it off.

As such, most people who become infected with the parasite are unaware of it.

Those who do become ill from T. gondii infection may experience flu-like symptoms – such as swollen lymph glands or muscle aches – that last for at least a month.

In severe cases, toxoplasmosis can cause damage to the eyes, brain, and other organs, though such complications usually only arise in people with weakened immune systems.

The new study, however, suggests there may be another dark side to T. gondii infection: it may lead to development of neurodegenerative disease in people who are predisposed to it.

To reach their findings, lead author Emma Wilson – an associate professor in the Division of Biomedical Sciences at the UC-Riverside School of Medicine – and colleagues focused on how T. gondii infection in mice affects glutamate production

How a build-up of glutamate can damage the brain

Glutamate is an amino acid released by nerve cells, or neurons. It is one of the brain’s most abundant excitatory neurotransmitters, aiding communication between neurons.

However, previous studies have shown that too much glutamate may cause harm; a build-up of glutamate is often found in individuals with traumatic brain injury (TBI) and people with certain neurodegenerative diseases, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

The researchers explain that excess glutamate accumulates outside of neurons, and this build-up is regulated by astrocytes – cells in the central nervous system (CNS).

Astrocytes use a glutamate transporter called GLT-1 in an attempt to remove excess glutamate from outside of neurons and convert it into a less harmful substance called glutamine, which cells use for energy.

“When a neuron fires, it releases glutamate into the space between itself and a nearby neuron,” explains Wilson. “The nearby neuron detects this glutamate, which triggers a firing of the neuron. If the glutamate isn’t cleared by GLT-1 then the neurons can’t fire properly the next time and they start to die.”


T. gondii increases glutamate by inhibiting GLT-1

n mice infected with T. gondii, the researchers identified an increase in glutamate levels.

They found that the parasite causes astrocytes to swell, which impairs their ability to regulate glutamate accumulation outside of neurons.

Furthermore, the parasite prevents GLT-1 from being properly expressed, which causes an accumulation of glutamate and misfiring of neurons. This may lead to neuronal death, and ultimately, neurodegenerative disease.

“These results suggest that in contrast to assuming chronic Toxoplasma infection as quiescent and benign, we should be aware of the potential risk to normal neurological pathways and changes in brain chemistry.” – Emma Wilson

Next, the researchers gave the infected mice an antibiotic called ceftriaxone, which has shown benefits in mouse models of ALS and a variety of CNS injuries.

They found the antibiotic increased expression of GLT-1, which led to a reduction in glutamate build-up and restored neuronal function.

Wilson says their study represents the first time that T. gondii has been shown to directly disrupt a key neurotransmitter in the brain.

“More direct and mechanistic research needs to be performed to understand the realities of this very common pathogen,” she adds.

While their findings indicate a link between T. gondii infection and neurodegenerative disease, Wilson says they should not be cause for panic.

“We have been living with this parasite for a long time,” she says. “It does not want to kill its host and lose its home. The best way to prevent infection is to cook your meat and wash your hands and vegetables. And if you are pregnant, don’t change the cat litter.”

The team now plans to further investigate what causes the reduced expression of GLT-1 in T. gondii infection.

http://www.medicalnewstoday.com/articles/310865.php