Category: Neurodegenerative Diseases

Categories : General Interest Neurodegenerative DiseasesTags :

Forming Supportive Connections for Multiple Sclerosis Sufferers

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This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis. Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

Multiple sclerosis (MS), an unpredictable, often disabling disease of the central nervous system with symptoms ranging from numbness and tingling to blindness and paralysis,1 is estimated to affect 2.8 million people around the world.2 Most people with MS are diagnosed between the ages of 20 and 50 years, with at least two to three times more women than men being diagnosed with the disease.1

Non Smit, Chairperson of Multiple Sclerosis South Africa, stresses the importance of generating extensive awareness to reach individuals with MS as well as healthcare providers and therapists. “This inclusive approach aims to establish a support system and platform that addresses crucial issues such as treatment accessibility, advocacy, epidemiology, and financial assistance,” says Smit.

The progress, severity, and specific symptoms of MS in any one person cannot yet be predicted; the disease varies greatly from person to person, and from time to time in the same person.1 Although MS can be very debilitating, it is estimated that about two-thirds of affected persons are still able to walk, although many may need an aid such as a cane or crutches.1

Dr Andile Mhlongo, Medical Advisor, Specialty Care at Sanofi South Africa, says: “There are no hard and fast rules about what life with MS will mean for each patient, because everybody experiences MS differently, depending on which part of the brain is affected. Symptoms range from problems with mobility to problems with vision, extreme tiredness and thinking – but these are just a few examples. It mostly affects young people, and if untreated can have a devasting impact on the lives of patients and their families.”

In terms of diagnosis, in early MS elusive symptoms that come and go might indicate any number of possible disorders. Some people have symptoms that are very difficult to interpret. While no single laboratory test is yet available to prove or rule out MS, magnetic resonance imaging (MRI) is a great help in reaching a definitive diagnosis.2

MS comes in several forms, including clinically isolated syndrome, relapsing-remitting MS, secondary progressive MS and primary progressive MS.3 The course is difficult to predict: some people may feel and seem healthy for many years after diagnosis, while others may be severely debilitated very quickly. Most people fit somewhere in-between.3

Clinically isolated syndrome (CIS) is the first episode of neurological symptoms experienced by a person, lasting at least 24 hours. They may experience a single sign or symptom, or more than one at the same time. CIS is an early sign of MS, but not everyone who experiences CIS goes on to develop MS.3

In relapsing-remitting MS (RRMS) people experience attacks or exacerbations of symptoms, which then fade or disappear. The symptoms may be new, or existing ones that become more severe. About 85% of people with MS are initially diagnosed with RRMS.3

Secondary progressive MS (SPMS) is a secondary phase that may develop years or even decades after diagnosis with RRMS. Most people who have RRMS will transition to SPMS, with progressive worsening of symptoms and no definite periods of remission.3

Primary progressive MS (PPMS) is diagnosed in about 10–15% of people with MS. They have steadily worsening symptoms and disability from the start, rather than sudden attacks or relapses followed by recovery.3

While there is no medicine that can cure MS, treatments are available which can modify the course of the disease. Sanofi has been a partner in the MS community since 2012, through the introduction of two treatments. One of these is an oral formulation for patients with relapsing forms of MS and the other is an infusion therapy for patients with rapidly evolving, severe relapsing-remitting MS.

“Sanofi continues to be a partner through research and development to bring about therapies to improve the management of this disease. Sanofi also supports various initiatives that bring education to patients and healthcare providers and the MS community in general,” says Mhlongo.

Advances in treating and understanding MS are being achieved daily and progress in research to find a cure is encouraging. In addition, many therapeutic and technological advances are helping people with MS to manage symptoms and lead more productive lives.2

For further information on MS, visit: https://www.sanofi.com/en/our-science/rd-focus-areas/neurology-rd or https://www.multiplesclerosis.co.za

References

  1. Multiple Sclerosis SA. What is multiple sclerosis? Available from: https://www.multiplesclerosis.co.za/ms-information/what-is-ms, accessed 29 May 2023.
  2. MS International Federation. About World MS Day. Available from: https://worldmsday.org/about/, accessed 29 May 2023.
  3. MS International Federation. Types of MS. Available from: https://www.msif.org/about-ms/types-of-ms/?gclid=Cj0KCQjw4NujBhC5ARIsAF4Iv6fOHSQYim5KoJidw7_9ig8HBcC3FRKWBmXViloS6H-__GPuavAsTgoaAuJjEALw_wcB, accessed 31 May 2023.
Categories : Neurodegenerative DiseasesTags :

Biomarkers Suggest That an Old Antihistamine Could Reverse MS

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Source: CC0

A decade after scientists identified an over-the-counter antihistamine as a treatment for multiple sclerosis, researchers have developed an approach to measure the drug’s effectiveness in repairing the brain, making it possible to also assess future therapies for the devastating disorder. Their study is published in PNAS.

The UC San Francisco researchers, led by physician-scientist Ari Green, MD, who together with neuroscientist Jonah Chan, PhD, first identified clemastine as a potential MS therapy, used MRI scans to study the drug’s impact on the brains of 50 participants in a clinical study.

In the brain, water trapped between the thin layers of myelin that wrap nerve fibers cannot move as freely as water floating between brain cells. This unique property of myelin allowed imaging experts to develop a technique to compare the difference in myelin levels before and after the drug was administered, by measuring the so-called myelin water fraction, or the ratio of myelin water to the total water content in brain tissue.

In their study, the researchers found that patients with MS who were treated with clemastine experienced modest increases in myelin water, indicating myelin repair. They also proved that the myelin water fraction technique, when focused on the right parts of the brain, could be used to track myelin recovery.

“This is the first example of brain repair being documented on MRI for a chronic neurological condition,” said Green. “The study provides the first direct, biologically validated, imaging-based evidence of myelin repair induced by clemastine. This will set the standard for future research into remyelinating therapies.”

Myelin increased even after medication was stopped

In the study, patients with MS who enrolled in the ReBUILD trial were divided into two groups: the first group received clemastine for the first three months of the study and the second group received clemastine only in months three to five. Using the myelin water fraction as a biomarker, the researchers found that myelin water increased in the first group after participants received the drug and continued to increase after clemastine was stopped. In the second group, the myelin water fraction showed decreases in myelin water in the first portion of the study, under the placebo, and a rebound after participants received clemastine.

The findings corroborate the results of a previous study with the same 50 patients that had found the allergy medication reduced delayed nerve signalling, potentially alleviating symptoms.

In the current study, researchers looked at the corpus callosum, a region of the brain with a high myelin content that connects the right and left hemispheres. They found that significant repair occurred outside the visible lesions typically associated with MS. This underscores the need to focus on myelin repair beyond these lesion sites.

Clemastine works in this setting by stimulating the differentiation of myelin-making stem cells. This places the medication a generation ahead of existing MS drugs that work by dampening the activity of the immune system, calming inflammation and reducing the risk of relapse. It still isn’t ideal, though, making the water fraction measurement an important tool in developing better therapeutics.

“Clemastine can only be partially effective at the doses we can use,” said Green, who is also a neuro-ophthalmologist and chief of the Division of Neuroimmunology and Glial Biology in the UCSF Department of Neurology. “It can be sedating, which may be especially undesirable in patients with MS. We are hopeful better medications will be developed, but clemastine has proven to be the tool to show remyelination is possible.”

Proposed future research will examine clemastine’s potential in treating brain injury in premature infants, who often experience myelin damage. 

Source: University of California San Francisco

Categories : Immune System Neurodegenerative DiseasesTags :

Scientists Strengthen Evidence Linking Autoimmunity and Schizophrenia

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Image by Pikisuperstar On Freepix

Links have been reported between schizophrenia and autoimmunity. In a study published in Brain Behavior and Immunity, Japanese researchers identified autoantibodies that target a ‘synaptic adhesion protein’, neurexin 1α, in a subset of patients with schizophrenia. When injected into mice, the autoantibodies caused many schizophrenia-related changes.

What is a synaptic protein, and why might it be linked to schizophrenia? Synaptic adhesion proteins are specialised proteins that bind to create physical connections between brain cells. These connections, called synapses, allow the cells to communicate by passing molecules back and forth. Both synapses and autoimmunity are known to be associated with schizophrenia, so the research team from Tokyo Medical and Dental University (TMDU) decided to investigate autoantibodies that target synaptic proteins in patients with schizophrenia.

“In around 2% of our patient population, we identified autoantibodies against the synaptic protein neurexin 1α, which is expressed by one cell in the synapse and binds to proteins known as neuroligins on the other cell in the synapse,” says lead author of the study Hiroki Shiwaku. “Once we had identified these autoantibodies, we wanted to see if they were able to cause schizophrenia-related changes.”

To do this, the researchers isolated autoantibodies from some of the patients with schizophrenia and injected them into the cerebrospinal fluid of mice, so that the autoantibodies would travel into the brain. In these mice, the autoantibodies blocked neurexin 1α and neuroligin binding and altered some related synaptic properties. The administration of these autoantibodies also resulted in fewer synapses in the brains of mice and schizophrenia-related behaviours, such as reduced social behaviour toward unfamiliar mice and reduced cognitive function.

“Together, our results strongly suggest that autoantibodies against neurexin 1α can cause schizophrenia-related changes, at least in mice,” explains Hiroki Shiwaku. “These autoantibodies may therefore represent a therapeutic target for a subset of patients with schizophrenia.”

Schizophrenia has a wide variety of both symptoms and treatment responses, and many patients have symptoms that are resistant to currently available treatment options. Therefore, the identification of possible disease-causing autoantibodies is important for improving symptom control in patients with schizophrenia. It is hoped that the results of this investigation will allow patients with autoantibodies that target neurexin 1α – all of whom were resistant to antipsychotic treatment in the present study — to better control their symptoms in the future.

Source: Tokyo Medical and Dental University

Categories : Neurodegenerative Diseases VaccinesTags :

Could the BCG Vaccine Reduce Alzheimer’s Risk?

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Photo by Mari Lezhava on Unsplash

The Bacillus Calmette-Guérin (BCG) for tuberculosis vaccine has a number additional beneficial effects, and is currently a recommended therapy for non–muscle-invasive bladder cancer. In a new study published in JAMA Network Open, treatment with the BCG vaccine was associated with a reduced risk of Alzheimer’s disease and related dementias.

Although previous research has suggested a link between the BCG vaccine and a lower risk of dementia, studies were limited by size, study design, or analytical methods. To conduct a more robust study, researchers followed 6467 individuals for up to 15 years after they were diagnosed with non–muscle-invasive bladder cancer.

The group included 3388 patients who underwent BCG vaccine treatment and 3079 who served as controls, matched by factors such as age, sex, and medical co-morbidities.

During follow-up, 202 patients in the BCG vaccine group and 262 in the control group developed Alzheimer’s disease and related dementias. The incidence was 8.8 per 1000 person-years and 12.1 per 1000 person-years in the respective groups.

Analyses revealed that treatment with the BCG vaccine was associated with a 20% lower risk of Alzheimer’s disease and related dementias. The protective association was greater in patients aged 70 years or older. Additionally, during follow-up, 751 patients in the BCG vaccine group and 973 in the control group died. Thus, treatment with BCG vaccine was associated with a 25% lower risk of death.

Study leader Marc Weinberg, MD, Ph.D., an Instructor in Psychiatry at MGH, said: “A vaccine like BCG, if proven effective, is a perfect example of a cost-effective, population-health–based solution to a devastating illness like Alzheimer’s disease. We are shifting our focus towards studying the potential benefits of BCG vaccination of older adults in Alzheimer’s disease–related clinical trials.”

If a causal link is found, it will be important to understand the mechanisms involved. Weinberg and his colleagues note that the BCG vaccine’s effects on the immune system may play a role.

Source: Massachusetts General Hospital

Categories : Neurodegenerative DiseasesTags :

Epstein–Barr Virus Antibodies may Trigger Multiple Sclerosis

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Source: CC0

Researchers at Karolinska Institutet have found further links between Epstein–Barr virus and multiple sclerosis. A study published in Science Advances shows that some individuals have antibodies against the virus that mistakenly attack a protein in the brain and spinal cord.

Many years ago, the Epstein–Barr virus (EBV), which infects most people early in life and then usually lies dormant was linked to multiple sclerosis (MS) but the reason remained a mystery. Increasing evidence, including two papers published in Science and Nature last year, suggests that EBV infection precedes MS and that antibodies against the virus may be involved. However, the molecular mechanisms seem to vary between patients and remain largely unknown.

“MS is an incredibly complex disease, but our study provides an important piece in the puzzle and could explain why some people develop the disease,” says Olivia Thomas, postdoctoral researcher at the Department of Clinical Neuroscience, Karolinska Institutet and shared first author of the paper. “We have discovered that certain antibodies against the Epstein-Barr virus, which would normally fight the infection, can mistakenly target the brain and spinal cord and cause damage.”

The researchers analysed blood samples from more than 700 patients with MS and 700 healthy controls. They found that antibodies that bind to a certain protein in the Epstein-Barr virus, EBNA1, can also bind to a similar protein in the brain and spinal cord called CRYAB, whose role is to prevent protein aggregation during conditions of cellular stress such as inflammation. These misdirected, cross-reactive antibodies may damage the nervous system and cause severe symptoms in MS patients, including problems with balance, mobility and fatigue. The antibodies were present in about 23 percent of MS patients and 7% of control individuals.

“This shows that, whilst these antibody responses are not required for disease development, they may be involved in disease in up to a quarter of MS patients,” says Olivia Thomas. “This also demonstrates the high variation between patients, highlighting the need for personalised therapies. Current therapies are effective at reducing relapses in MS but unfortunately, none can prevent disease progression.”

“We are now expanding our research to investigate how T cells fight EBV infection and how these immune cells may damage the nervous system in multiple sclerosis and contribute to disease progression,” says joint first author of the paper Mattias Bronge, affiliated researcher at the Department of Clinical Neuroscience, Karolinska Institutet.

Source: Karolinska Institutet

Categories : Gender Neurodegenerative DiseasesTags :

Sex Differences in Alzheimer’s Rates may be Caused by Stress Responses

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Photo by Ravi Patel on Unsplash

Women are about twice as likely as men to be diagnosed with Alzheimer’s disease. Some of that is age: women outlive men in most countries, and advanced age is the strongest risk factor for Alzheimer’s. But not all of it explains the excess risk.

One such factor may be stress may be one such reason. A study published in Brain shows that the effect stress has on the brain differs by sex, at least in mice. In stressful situations, levels of the Alzheimer’s protein amyloid beta rises sharply in the brains of females but not males. In addition, the researchers identified a molecular pathway that is active in brain cells from female mice but not male mice, and showed that it accounts for the divergent responses to stress.

The findings, from researchers at Washington University School of Medicine in St. Louis, add to a growing collection of evidence that sex matters in health and disease. From cancer to heart disease to arthritis, scientists have found differences between males and females that could potentially affect how men and women respond to efforts to prevent or treat chronic diseases.

“How women respond to stress versus how men respond to stress is an important area of research that has implications for not just Alzheimer’s disease but other conditions, too,” said co-corresponding author Carla M. Yuede, PhD, an associate professor of psychiatry. “In recent years, the National Institutes of Health (NIH) has prioritized understanding sex differences in medicine. Stress is one area in which you can clearly see a difference between males and females. This study shows that reducing stress may be more beneficial for women than men, in terms of lowering the risk of Alzheimer’s disease.”

Stress falls into the category of socioeconomic risk factors, along with factors such as depression and social isolation, that together account for an estimated 8% of the risk of developing Alzheimer’s. That risk calculation, however, doesn’t take sex into account. Women consistently report higher levels of stress than men, and it affects them differently.

Corresponding author John Cirrito, PhD, an associate professor of neurology; Yuede; and first author Hannah Edwards, a graduate student in Cirrito’s lab, reasoned that stress also may affect women’s brains differently than men’s, and these differences may help explain the sex imbalance in Alzheimer’s disease.

To find out, they measured levels of amyloid beta in the brains of mice every hour for 22 hours, beginning eight hours before the mice experienced stress. The experience was equally stressful for male and female mice, as measured by the levels of stress hormones in their blood. But the responses in their brains were not the same.

In female mice, amyloid beta levels rose significantly within the first two hours and stayed elevated through the end of the monitoring period. In male mice, brain amyloid levels did not change overall, although about 20% of them did show a delayed and weak rise in amyloid levels.

Further experiments revealed that the difference comes down to a cellular stress response pathway in brain cells. Stress causes the release of a hormone known as corticotropin releasing factor. Neurons from female rodents take up the stress hormone, triggering a cascade of events that results in increasing levels of amyloid beta in the brain. In contrast, neurons from male rodents lack the ability to take up the stress hormone. It is not known whether there are similar sex differences in how human neurons take up stress hormones.

“There’s a fundamental biological difference between males and females in how they respond to stress at the cellular level, in both mice and people,” Cirrito said. “We don’t think that stress is the sole factor driving the sex difference in Alzheimer’s disease. There are many other differences between men and women – in hormones, lifestyle, other diseases they have – that undoubtedly contribute in some way. But that stress is driving one aspect of this sex difference I think is very likely.”

Source: Washington University School of Medicine

Categories : Neurodegenerative DiseasesTags :

Gene Silencing Treatment Lowers Tau Proteins in Alzheimer’s Patients

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Neurons in the brain of an Alzheimer’s patient, with amyloid plaques caused by tau proteins. Credit: NIH

In a preliminary trial, a new ‘gene silencing’ treatment has been able to safely and successfully lower levels of the harmful tau protein known to cause the disease. This success, published in Nature Medicine, demonstrates that a ‘gene silencing’ approach could work in dementia and Alzheimer’s disease.

The approach uses a drug called BIIB080 (/IONIS-MAPTRx), which is an antisense oligonucleaotide (used to stop RNA producing a protein), to ‘silence’ the gene coding for the tau protein – known as the microtubule-associated protein tau (MAPT) gene. This prevents the gene from being translated into the protein in a doseable and reversible way. It also reduces production of that protein, altering the course of disease.

Further trials will be needed in larger groups of patients to determine whether this leads to clinical benefit, but the phase 1 results are the first indication that this method has a biological effect.

There are currently no treatments targeting tau. The drugs aducanumab and lecanemab – recently approved for use in some situations by the FDA – target a separate disease mechanism in AD, the accumulation of amyloid plaques.

The phase 1 trial enrolled 46 patients with an average age of 66, and looked at the safety of BIIB080, what it does in the body, and how well it targets the MAPT gene. The trial compared three doses of the drug, given by intrathecal injection (an injection into the nervous system via the spinal canal), with the placebo.

Results show that the drug was well tolerated, with all patients completing the treatment period and over 90% completing the post-treatment period.

Patients in both the treatment and placebo groups experienced either mild or moderate side effects – the most common being a headache after injection of the drug. However, no serious adverse events were seen in patients given the drug.

The research team also looked at two forms of the tau protein in the central nervous system (CNS) – a reliable indicator of disease – over the duration of the study.

They found a greater than 50% reduction in levels of total tau and phosphor tau concentration in the CNS after 24 weeks in the two treatment groups that received the highest dose of the drug.

Consultant neurologist Dr Catherine Mummery, who led the study, said: “We will need further research to understand the extent to which the drug can slow progression of physical symptoms of disease and evaluate the drug in older and larger groups of people and in more diverse populations.

“But the results are a significant step forward in demonstrating that we can successfully target tau with a gene silencing drug to slow – or possibly even reverse – Alzheimer’s disease, and other diseases caused by tau accumulation in the future.”

Source: Imperial College London

Categories : Neurodegenerative DiseasesTags :

A Sleeping Pill Lowers Alzheimer’s Protein Levels

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An early sign of Alzheimer’s disease is sleep disturbance – many people eventually diagnosed with Alzheimer’s start experiencing difficulty falling and staying asleep years before the emergence of cognitive problems such as memory loss and confusion. In a vicious circle, Alzheimer’s disease disrupts sleep, and poor sleep accelerates harmful changes to the brain.

Now, researchers at Washington University School of Medicine in St. Louis have identified a possible way to help break that cycle. Published in Annals of Neurology, a small, two-night study has shown that people who took a sleeping pill before bed experienced a drop in the levels of key Alzheimer’s proteins – a good sign, since higher levels of such proteins tracks with worsening disease. The study, which involved a sleeping aid known as suvorexant that is already approved by the Food and Drug Administration (FDA) for insomnia, hints at the potential of sleep medications to slow or stop the progression of Alzheimer’s disease, although much more work is needed to confirm the viability of such an approach.

“This is a small, proof-of-concept study. It would be premature for people who are worried about developing Alzheimer’s to interpret it as a reason to start taking suvorexant every night,” said senior author Brendan Lucey, MD, an associate professor of neurology and director of Washington University’s Sleep Medicine Center. “We don’t yet know whether long-term use is effective in staving off cognitive decline, and if it is, at what dose and for whom. Still, these results are very encouraging. This drug is already available and proven safe, and now we have evidence that it affects the levels of proteins that are critical for driving Alzheimer’s disease.”

Suvorexant belongs to a class of insomnia medications known as dual orexin receptor antagonists. Orexin is a natural biomolecule that promotes wakefulness. When orexin is blocked, people fall asleep. Three orexin inhibitors have been approved by the FDA, and more are in the pipeline.

Alzheimer’s disease begins when plaques of the protein amyloid beta start building up in the brain. After years of amyloid accumulation, a second brain protein, tau, begins to form tangles that are toxic to neurons. People with Alzheimer’s disease start experiencing cognitive symptoms such as memory loss around the time tau tangles become detectable.

Lucey and colleagues were among the first to show in people that poor sleep is linked to higher levels of both amyloid and tau in the brain. The question remains as to whether good sleep has the opposite effect – a reduction in amyloid and tau levels, and a halt in or reversal of the progress of Alzheimer’s disease – but mouse studies with orexin inhibitors have been promising.

As a first step to assess the effect of orexin inhibitors on people, Lucey and colleagues recruited 38 participants ages 45 to 65 and with no cognitive impairments to undergo a two-night sleep study. The participants were given a lower dose (10 mg) of suvorexant (13 people), a higher dose (20 mg) of suvorexant (12 people) or a placebo (13 people) at 9 p.m. and then went to sleep in a clinical research unit at Washington University. Researchers withdrew a small amount of cerebrospinal fluid via spinal tap every two hours for 36 hours, starting one hour before the sleeping aid or placebo was administered, to measure how amyloid and tau levels changed over the next day and a half.

Amyloid levels dropped 10% to 20% in the cerebrospinal fluid of people who had received the high dose of suvorexant compared to people who had received placebo, and the levels of a key form of tau known as hyperphosphorylated tau dropped 10% to 15%, compared to people who had received placebo. Both differences are statistically significant. There was not a significant difference between the people who received a low dose of suvorexant and those who received the placebo.

By 24 hours after the first dose, hyperphosphorylated tau levels in the high-dose group had risen, while amyloid levels remained low compared to the placebo group. A second dose of suvorexant, administered on the second night, sent the levels of both proteins down again for people in the high-dose group.

“If we can lower amyloid every day, we think the accumulation of amyloid plaques in the brain will decrease over time,” Lucey said. “And hyperphosphorylated tau is very important in the development of Alzheimer’s disease, because it’s associated with forming tau tangles that kill neurons. If you can reduce tau phosphorylation, potentially there would be less tangle formation and less neuronal death.”

The study is preliminary, since it only looked at the effect of two doses of the drug in a small group of participants. Lucey has studies underway to assess the longer-term effects of orexin inhibitors in people at higher risk of dementia.

“Future studies need to have people taking these drugs for months, at least, and measuring the effect on amyloid and tau over time,” Lucey said. “We’re also going to be studying participants who are older and may still be cognitively healthy, but who already have some amyloid plaques in their brains. This study involved healthy middle-aged participants; the results may be different in an older population.

“I’m hopeful that we will eventually develop drugs that take advantage of the link between sleep and Alzheimer’s to prevent cognitive decline,” he continued. “We’re not quite there yet. At this point, the best advice I can give is to get a good night’s sleep if you can, and if you can’t, to see a sleep specialist and get your sleep problems treated.”

Source: Washington University School of Medicine

Categories : Neurodegenerative DiseasesTags :

A Genetic Treatment for ALS That Restores Key Protein May Be Possible

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DNA repair
Source: Pixabay/CC0

In virtually all persons with amyotrophic lateral sclerosis (ALS) and in up to half of all cases of Alzheimer’s disease (AD) and frontotemporal dementia, a protein called TDP-43 is lost from its normal location in the nucleus of the cell. In turn, this triggers the loss of stathmin-2, a protein crucial to regeneration of neurons and the maintenance of their connections to muscle fibres.

Writing in Science, a team of scientists demonstrate that stathmin-2 loss can be rescued using designer DNA drugs that restore normal processing of protein-encoding RNA.

“With mouse models we engineered to misprocess their stathmin-2 encoding RNAs, like in these human diseases, we show that administration of one of these designer DNA drugs into the fluid that surrounds the brain and spinal cord restores normal stathmin-2 levels throughout the nervous system,” said senior study author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences and Cellular and Molecular Medicine at University of California San Diego School of Medicine.

Cleveland is broadly credited with developing the concept of designer DNA drugs, which act to either turn on or turn off genes associated with many degenerative diseases of the aging human nervous system, including ALS, AD, Huntington’s disease and cancer.

Several designer DNA drugs are currently in clinical trials for multiple diseases. One such drug has been approved to treat a childhood neurodegenerative disease called spinal muscular atrophy.

The new study builds upon ongoing research by Cleveland and others regarding the role and loss of TDP-43, a protein associated with ALS, AD and other neurodegenerative disorders. In ALS, TDP-43 loss impacts the motor neurons that innervate and trigger contraction of skeletal muscles, causing them to degenerate, eventually resulting in paralysis.

“In almost all of instances of ALS, there is aggregation of TDP-43, a protein that functions in maturation of the RNA intermediates that encode many proteins. Reduced TDP-43 activity causes misassembly of the RNA-encoding stathmin-2, a protein required for maintenance of the connection of motor neurons to muscle,” said Cleveland.

“Without stathmin-2, motor neurons disconnect from muscle, driving paralysis that is characteristic of ALS. What we have now found is that we can mimic TDP-43 function with a designer DNA drug, thereby restoring correct stathmin-2 RNA and protein level in the mammalian nervous system.”

Specifically, the researchers edited genes in mice to contain human STMN2 gene sequences and then injected antisense oligonucleotides – small DNA or RNA pieces that can bind to specific RNA molecules, blocking their ability to make a protein or changing how their final RNAs are assembled – into cerebral spinal fluid. The injections corrected STMN2 pre-mRNA misprocessing and restored stathmin-2 protein expression fully independent of TDP-43 function.

“Our findings lay the foundation for a clinical trial to delay paralysis in ALS by maintaining stathmin-2 protein levels in patients using our designer DNA drug,” Cleveland said.

Source: University of California – San Diego

Categories : Cardiovascular Disease Neurodegenerative DiseasesTags :

Atrial Fibrillation Linked to Dementia Risk

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Source: American Heart Association

A large representative study found that individuals with newly diagnosed atrial fibrillation had a modestly elevated risk of developing dementia. The Journal of the American Heart Association study found that this risk was higher in younger adults and those without chronic kidney disease, but did not substantially vary across sex, race, or ethnicity.

In this study of nearly 200 000 adults, incidence rates for dementia over a median follow-up of 3.3 years were 2.79 versus 2.04 per 100 person-years in individuals with versus without atrial fibrillation, respectively. (This means that over one year, there would be an average of 2.79 dementia diagnoses among 100 people with atrial fibrillation and 2.04 diagnoses among 100 people without atrial fibrillation. This translates to 279 per 10 000 and 204 per 10 000.)

After adjustments, atrial fibrillation was associated with a 13% higher risk of dementia. Adults aged <65 years had a 65% higher risk compared with older adults, those without chronic kidney disease had a 14% higher risk than those with chronic kidney disease.

“These data highlight a possible link between atrial fibrillation and risk of subsequent dementia in certain populations. Further studies are needed to understand the mechanisms to explain this association, which may inform the use of treatments for atrial fibrillation,” said corresponding author Nisha Bansal, MD, MAS, of the University of Washington School of Medicine.

Source: Wiley