Category: Neurodegenerative Diseases

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First-of-its-kind Technology Helps Man with ALS ‘Speak’ in Real Time

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An investigational brain-computer interface (BCI) allows the study participant to communicate through a computer. Credit: UC Davis

Researchers at the University of California, Davis, have developed an investigational brain-computer interface that holds promise for restoring the ability to hold real-time conversations to people who have lost the ability to speak due to neurological conditions.

In a new study published in the scientific journal Nature, the researchers demonstrate how this new technology can instantaneously translate brain activity into voice as a person tries to speak – effectively creating a digital vocal tract with no detectable delay.

The system allowed the study participant, who has amyotrophic lateral sclerosis (ALS), to “speak” through a computer with his family in real time, change his intonation and “sing” simple melodies.

“Translating neural activity into text, which is how our previous speech brain-computer interface works, is akin to text messaging. It’s a big improvement compared to standard assistive technologies, but it still leads to delayed conversation. By comparison, this new real-time voice synthesis is more like a voice call,” said Sergey Stavisky, senior author of the paper and an assistant professor in the UC Davis Department of Neurological Surgery. Stavisky co-directs the UC Davis Neuroprosthetics Lab.

“With instantaneous voice synthesis, neuroprosthesis users will be able to be more included in a conversation. For example, they can interrupt, and people are less likely to interrupt them accidentally,” Stavisky said.

Decoding brain signals at heart of new technology

The man is enrolled in the BrainGate2 clinical trial at UC Davis Health. His ability to communicate through a computer has been made possible with an investigational brain-computer interface (BCI). It consists of four microelectrode arrays surgically implanted into the region of the brain responsible for producing speech.

These devices record the activity of neurons in the brain and send it to computers that interpret the signals to reconstruct voice.

“The main barrier to synthesising voice in real-time was not knowing exactly when and how the person with speech loss is trying to speak,” said Maitreyee Wairagkar, first author of the study and project scientist in the Neuroprosthetics Lab at UC Davis. “Our algorithms map neural activity to intended sounds at each moment of time. This makes it possible to synthesise nuances in speech and give the participant control over the cadence of his BCI-voice.”

Instantaneous, expressive speech with BCI shows promise

The brain-computer interface was able to translate the study participant’s neural signals into audible speech played through a speaker very quickly – one-fortieth of a second. This short delay is similar to the delay a person experiences when they speak and hear the sound of their own voice.

The technology also allowed the participant to say new words (words not already known to the system) and to make interjections. He was able to modulate the intonation of his generated computer voice to ask a question or emphasize specific words in a sentence.

The participant also took steps toward varying pitch by singing simple, short melodies.

His BCI-synthesized voice was often intelligible: Listeners could understand almost 60% of the synthesized words correctly (as opposed to 4% when he was not using the BCI).

Real-time speech helped by algorithms

The process of instantaneously translating brain activity into synthesized speech is helped by advanced artificial intelligence algorithms.

The algorithms for the new system were trained with data collected while the participant was asked to try to speak sentences shown to him on a computer screen. This gave the researchers information about what he was trying to say.

The electrodes measured the firing patterns of hundreds of neurons. The researchers aligned those patterns with the speech sounds the participant was trying to produce at that moment in time. This helped the algorithm learn to accurately reconstruct the participant’s voice from just his neural signals.

Clinical trial offers hope

“Our voice is part of what makes us who we are. Losing the ability to speak is devastating for people living with neurological conditions,” said David Brandman, co-director of the UC Davis Neuroprosthetics Lab and the neurosurgeon who performed the participant’s implant.

“The results of this research provide hope for people who want to talk but can’t. We showed how a paralyzed man was empowered to speak with a synthesized version of his voice. This kind of technology could be transformative for people living with paralysis.”

Brandman is an assistant professor in the Department of Neurological Surgery and is the site-responsible principal investigator of the BrainGate2 clinical trial.

Limitations

The researchers note that although the findings are promising, brain-to-voice neuroprostheses remain in an early phase. A key limitation is that the research was performed with a single participant with ALS. It will be crucial to replicate these results with more participants, including those who have speech loss from other causes, such as stroke.

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New Immune Solution Suggests Taking the STING out of Alzheimer’s

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A new way of thinking about Alzheimer’s disease has yielded a discovery that could be the key to stopping the cognitive decline seen in Alzheimer’s and other neurodegenerative diseases.

University of Virginia School of Medicine scientists have been investigating the possibility that Alzheimer’s is caused, at least in part, by the immune system’s wayward attempts to fix DNA damage in the brain. Their research reveals that an immune molecule called STING drives the formation of the harmful plaques and protein tangles thought responsible for Alzheimer’s. Blocking the molecule protected lab mice from mental decline, the researchers say.

An important player in the brain’s immune system, STING also may be a key contributor to Parkinson’s disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), dementia and other memory-robbing conditions. That means that developing treatments to control its activity could have far-reaching benefits for many patients facing now-devastating diagnoses.

“Our findings demonstrate that the DNA damage that naturally accumulates during aging triggers STING-mediated brain inflammation and neuronal damage in Alzheimer’s disease,” said researcher John Lukens, PhD, director of UVA’s Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases. “These results help to explain why aging is associated with increased Alzheimer’s risk and uncover a novel pathway to target in the treatment of neurodegenerative diseases.”

Alarming Trends in Alzheimer’s

Alzheimer’s is a growing problem, with researchers working frantically to find ways to better understand and treat the condition.

The causes of Alzheimer’s remain murky, but scientists are increasingly coming to appreciate the role of the immune system in the disease’s development. STING is part of that immune response; the molecule helps direct the clearance of viruses and stressed cells harboring DNA damage.

While STING is an important defender of the brain, it can also become hyperactive and cause harmful inflammation and tissue damage. That had Lukens and his team eager to determine what part it could be playing in Alzheimer’s. Blocking the molecule’s activity in lab mice, they found, helped prevent Alzheimer’s plaque formation, altered the activity of immune cells called microglia and redirected the workings of important genes, among other effects.

“We found that removing STING dampened microglial activation around amyloid plaques, protected nearby neurons from damage and improved memory function in Alzheimer’s model mice,” said researcher Jessica Thanos, part of UVA’s Department of Neuroscience and Center for Brain Immunology and Glia (BIG Center). “Together, these findings suggest that STING drives detrimental immune responses in the brain that exacerbate neuronal damage and contribute to cognitive decline in Alzheimer’s disease.”

Promising Treatment Target

While scientists have been investigating other molecules thought to be important in Alzheimer’s, STING makes for a particularly attractive target for developing new treatments, the UVA Health researchers say. That’s because blocking STING appears to slow both the buildup of amyloid plaques and the development of tau tangles, the two leading candidates for the cause of Alzheimer’s. Other molecules lack that robust involvement, and, further, could be targeted only at very specific – and very limited – stages in the disease’s progression.

“We are only beginning to understand the complex role of innate immune activation in the brain, and this is especially true in both normal and pathological aging,” Thanos said. “If we can pinpoint which cells and signals sustain that activation, we will be in a much better position to intervene effectively in disease.”

While Lukens’ pioneering research has opened new doors in the fight against Alzheimer’s, much more work will need to be done to translate the findings into treatments. For example, scientists will need to better understand STING’s roles in the body – such as in the immune system’s response to cancer – to ensure any new treatment doesn’t cause unwanted side effects.

But those are the types of big questions that Lukens and his collaborators at the Harrison Family Translational Research Center are eager to tackle as part of their efforts to fast-track new treatments and, eventually, they hope, cures.

“Our hope is that this work moves us close to finding safer and more effective ways to protect the aging brain, as there is an urgent need for treatments that can slow or prevent neuronal damage in Alzheimer’s,” Lukens said. “Shedding light on how STING contributes to that damage may help us target similar molecules and ultimately develop effective disease-modifying treatments.”

Source: University of Virginia Health System

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Common Gene Variant Doubles Dementia Risk for Men

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New research has found that men who carry a common genetic variant are twice as likely to develop dementia in their lifetime compared to women. The research, published in Neurology, used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial to investigate whether people who had variants in the haemochromatosis (HFE) gene, which is critical for regulating iron levels in the body, might be at increased risk of dementia.

Co-author Professor John Olynyk, from the Curtin Medical School, said one in three people carry one copy of the variant, known as H63D, while one in 36 carry two copies.

“Having just one copy of this gene variant does not impact someone’s health or increase their risk of dementia. However, having two copies of the variant more than doubled the risk of dementia in men, but not women,” Professor Olynyk said.

“While the genetic variant itself cannot be changed, the brain pathways which it affects – leading to the damage that causes dementia – could potentially be treated if we understood more about it.”

Professor Olynyk said further research was needed to investigate why this genetic variant increased the risk of dementia for males but not females.

“The HFE gene is routinely tested for in most Western countries including Australia when assessing people for haemochromatosis – a disorder that causes the body to absorb too much iron. Our findings suggest that perhaps this testing could be offered to men more broadly,” Professor Olynyk said.

“While the HFE gene is critical for controlling iron levels in the body, we found no direct link between iron levels in the blood and increased dementia risk in affected men.

“This points to other mechanisms at play, possibly involving the increased risk of brain injury from inflammation and cell damage in the body.”

The ASPREE trial was a double-blind, randomised, placebo-controlled trial of daily low-aspirin in 19 114 healthy older people in Australia and the USA. Primarily undertaken to evaluate the risks versus benefits of daily low-dose aspirin in this cohort, it created a treasure trove of healthy ageing data that has underpinned a wealth of research studies.

Source: Curtin University

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Autism Linked to Elevated Risk of Parkinson’s Disease

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People with an autism diagnosis are at a higher risk of developing Parkinson’s disease early in life, according to a large-scale study from Karolinska Institutet. The researchers believe that the two conditions can share underlying biological mechanisms.

The study, published in JAMA Neurology, is based on registry data from over two million people born in Sweden between 1974 and 1999 who were followed from the age of 20 up to the end of 2022.

The researchers interrogated a possible connection between the neuropsychiatric diagnosis Autism Spectrum Disorder (ASD), which affects an individual’s thought processes, behaviour and interpersonal communication, and early-onset Parkinson’s disease, a condition that affects locomotion and movement.

Possible dopamine involvment

The results show that people with an autism diagnosis were four times more likely to develop Parkinson’s disease than people without such a diagnosis, a correlation that remained when controlling for socioeconomic status, a genetic predisposition for mental illness or Parkinson’s disease and other such factors.

“This indicates that there can be shared biological drivers behind ASD and Parkinson’s disease,” says first author Weiyao Yin at the Department of Medical Epidemiology and Biostatistics. “One hypothesis is that the brain’s dopamine system is affected in both cases, since the neurotransmitter dopamine plays an important part in social behaviour and motion control.”

It is well-known that dopamine-producing neurons are degraded in Parkinson’s disease. Previous studies have also shown that dopamine is possibly implicated in autism, but more research needs to be done to confirm this.

“We hope that our results will eventually help to bring greater clarity to the underlying causes of both ASD and Parkinson’s disease,” says Dr Yin.

Medical checkups are vital

Depression and the use of antidepressants are common in people with autism, as are antipsychotic drugs, which are known for being able to cause Parkinson’s-like symptoms. When the researchers adjusted for these factors, the correlation between ASD and the later development of Parkinson’s disease was less salient, but the risk was still double.

The researchers point out that they only analysed early-onset Parkinson’s disease before the age of 50 and that the average age of participants by the end of the study was 34. The incidence of Parkinson’s disease was therefore very low. Future studies will need to examine if the elevated risk persists into older age. 

“The healthcare services need to keep people with ASD – a vulnerable group with high co-morbidity and a high use of psychotropics – under long-term observation,” says last author Sven Sandin, statistician and epidemiologist at the Department of Medical Epidemiology and Biostatistics. “At the same time, it’s important to remember that a Parkinson’s diagnosis before the age of 50 is very rare, including for people with autism.”

Source: Karolinska Institutet

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Unlocking New Areas of the Brain for Stimulation in Parkinson’s

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Deep brain stimulation illustration. Credit: NIH

People with Parkinson’s disease increasingly lose their mobility over time and are eventually unable to walk. Hope for these patients rests on deep brain stimulation. In a recent study, researchers at Ruhr University Bochum and Philipps-Universität Marburg, Germany, investigated whether and how stimulation of a certain region of the brain can have a positive impact on ambulatory ability and provide patients with a better quality of life. To do so, the researchers used a technique in which the nerve cells are activated and deactivated via light. Their report appeared in the journal Scientific Reports.

Improving ambulatory ability

If medication is no longer sufficient in alleviating restricted mobility in the advanced stage of Parkinson’s disease, one alternative is deep brain stimulation. An electrical pulse emitter is implanted within the brain, such as in the subthalamic nucleus, which is functionally part of the basal ganglia system. 

The group under Dr Liana Melo-Thomas from Philipps-Universität Marburg was able to show in previous studies on rats that stimulation of the inferior colliculus, chiefly known for processing auditory input, can be used to overcome mobility restrictions. “There are indications that stimulation of this region of the brain leads to activation of the mesencephalic locomotor region, or MLR,” says Melo-Thomas.

Interestingly, the colliculus inferior – unlike the basal ganglia –is not affected by Parkinson’s disease. However, the research group under Melo-Thomas discovered that its stimulation activates alternative motor pathways and can improve patients’ mobility.

The current study aimed to further investigate this activating influence of the inferior colliculus on the MLR. “We suspected that this would have a positive effect on ambulatory ability,” says Melo-Thomas.

Optically influencing nerve cells

The Marburg group led by Professor Rainer Schwarting sought support by Dr Wolfgang Kruse from the Department of General Zoology and Neurobiology at Ruhr University Bochum. The team in Bochum led by Professor Stefan Herlitze played a significant role in co-developing the methods of optogenetics.

While doing so, the researchers ensure that the nerve cells of genetically modified test animals produce a light-sensitive protein in interesting regions of the brain. Light that reaches these nerve cells via small, implanted optical fibres allows the researchers to activate or inhibit them specifically. “This method is thus much more precise than electrical stimulation, which always affects the area around the cells as well,” says Kruse.

For the first time, the effect of the stimulation was directly documented with electrophysiological measurements of neuronal activity in the target structures. A multi-electrode system originally developed at Philipps-Universität Marburg was used for this purpose. By combining these methods, the researchers were able to directly understand the effect of the stimulation. Parallel measurement with up to four electrodes is also highly efficient, allowing minimisation of the number of animals used. Behavioural effects that can be triggered by the stimulation were monitored in conscious animals.

Stimulation of the inferior colliculus provides the desired effect

Optogenetic stimulation in the inferior colliculus predominantly triggered the expected increase in neuronal activity within it. “Simultaneous measurements in the deeper MLR region showed increased activity in the majority of cells, although nearly one quarter of the cells were inhibited by the additional activity in the inferior colliculus,” reports Kruse. The activation of individual nerve cells occurred with an average delay of 4.7 milliseconds, indicating a functional synaptic interconnection between the inferior colliculus and MLR.

Foundations for new types of therapy

Investigating circuits outside of the basal ganglia that are affected by Parkinson’s disease is a promising step in the search for a new therapeutic approach to alleviating motor deficits resulting from the disease. Such is the case with the connection between the inferior colliculus and the MLR that was investigated for this study.

“Even if the path toward new therapeutic approaches to alleviating the symptoms of Parkinson’s disease still appears long, such foundational research is immensely important,” emphasises Kruse. The exact mechanisms that lead to the observed relief of symptoms with deep brain stimulation in the basal ganglia are not fully understood. Further investigation of the underlying interconnections may provide new insight that could optimise therapy in the long term.

Source: Ruhr-University Bochum

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Protein Clues in the Hunt for the Cause of Frontotemporal Dementia

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Dementia usually affects older people, so when it occurs in middle age, it can be hard to recognise. The most common form is frontotemporal dementia (FTD), which is often mistaken for depression, schizophrenia, or Parkinson’s disease before the correct diagnosis is reached.

Now, as part of an NIH-funded study, researchers at UC San Francisco have found some clues about how FTD develops that could lead to new diagnostics and get more patients into clinical trials. The findings appear in Nature Aging on May 16.

The team measured more than 4000 proteins found in spinal tap fluid from 116 FTD patients and compared them to those from 39 of their healthy relatives. All 116 patients had inherited forms of FTD, enabling researchers to study the disease in living people with confirmed diagnosis, something that isn’t possible in non-inherited FTD cases, which can only be confirmed after death.

The composition of the proteins that changed in FTD suggest that these patients have problems with RNA regulation along with defects that affect connections in their brains. These proteins, researchers think, could be the first specific markers for FTD that emerge as the disease develops in middle age.

FTD is the most common form of dementia for people under 60. Because it occurs in younger people, it is often misdiagnosed as depression, early-onset Alzheimer’s, Parkinson’s, or a psychiatric condition. It takes an average of 3.6 years for patients to get an accurate diagnosis. There is no cure, and there are no treatments to slow or stop disease progression. It is distinct from Alzheimer’s in 3 major ways:

  • FTD features a gradual decline in behavior, language, or movement, but memory is intact.
  • It usually strikes younger people, between 45 and 65 years of age, and is less likely to strike after 65.
  • It’s less common, affecting 60 000 people in the U.S. (Alzheimer’s affects 6.7 million Americans).

“FTD affects people in the prime of their lives, stripping them of their independence,” said Rowan Saloner, PhD, professor in the UCSF Memory and Aging Center and corresponding author of the paper. “But there’s no definitive way to diagnose it in living patients, unlike other dementias like Alzheimer’s disease.”

“If we’re able to identify FTD early on, perhaps using some of the proteins we’ve identified, we can direct patients to the right resources, get them into the right therapeutic trials, and, ultimately, we hope, provide them with precision treatments.”

Source: University of California – San Francisco

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The Hidden Connection Between Herpes and Alzheimer’s

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A new study has uncovered a surprising link between Alzheimer’s disease and Herpes Simplex Virus-1 (HSV-1).

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

A new study led by Dr Or Shemesh at the Hebrew University of Jerusalem has uncovered a surprising connection between Alzheimer’s disease and the Herpes Simplex Virus-1 (HSV-1). The research team used advanced techniques to identify 19 HSV-1-related proteins in the brains of people with Alzheimer’s, across all stages of the disease. This discovery, published in Cell Reports, strengthens the growing evidence that infections like HSV-1 might play a role in the development and progression of Alzheimer’s.

One key finding was the increased activity of a herpesvirus protein called ICP27, which became more prominent as the disease advanced. This protein was found to occupy the same space as tau, a brain protein that becomes harmful when it undergoes changes in Alzheimer’s disease, but it did not appear near amyloid plaques, another hallmark of the illness. This suggests that HSV-1 may directly affect tau and contribute to the changes seen in Alzheimer’s.

The team’s experiments with human brain organoids derived from stem cells revealed that HSV-1 infection can increase tau modifications at specific sites linked to Alzheimer’s disease.

Remarkably, these modifications seem to help protect brain cells early on by reducing the amount of virus and preventing cell death. However, as the disease progresses, these same processes may contribute to the brain damage associated with Alzheimer’s. The study also highlighted the role of Alzheimer’s pathologies as part of the brain’s natural immune system in this process, focusing on a pathway called cGAS-STING, which influences tau changes.

Dr Shemesh explained, “Our research shows how HSV-1 interacts with the brain and influences the pathologies of Alzheimer’s disease. Early on, the changes in tau may protect brain cells by limiting the virus, but as the disease advances, these same changes could lead to more harm and accelerate neurodegeneration.”

This study provides new insights into how infections and the brain’s immune response may be involved in Alzheimer’s disease. It suggests that targeting viral activity or modifying the immune system’s response could offer new treatment possibilities. While more research is needed to fully understand these processes, these findings open the door to innovative ways to slow or stop the progression of this devastating disease.

The research paper titled “Anti-Herpetic Tau Preserves Neurons vis the cGAS-STING-TBK1 Pathway in Alzheimer’s Disease” is now available in Cell Reports and can be accessed at https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01460-8 

Source: The Hebrew University of Jerusalem

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Alzheimer’s Drug Lecanemab Well Tolerated in Real-world Use

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Side effects of lecanemab are manageable, study finds

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The Food and Drug Administration’s approval in 2023 of lecanemab – a novel Alzheimer’s therapy shown in clinical trials to modestly slow disease progression – was met with enthusiasm by many in the field as it represented the first medication of its kind able to influence the disease. But side effects of brain swelling and bleeding emerged during clinical trials that have left some patients and physicians hesitant about the treatment. [Especially considering its $26 500 per year cost – Ed.]

Medications can have somewhat different effects once they are released into the real world with broader demographics. Researchers at Washington University School of Medicine in St. Louis set out to study the adverse events associated with lecanemab treatment in their clinic patients and found that significant adverse events were rare and manageable.

Consistent with the results from carefully controlled clinical trials, researchers found that only 1% of patients experienced severe side effects that required hospitalisation. Patients in the earliest stage of Alzheimer’s with very mild symptoms experienced the lowest risk of complications, the researchers found, helping to inform patients and clinicians as they navigate discussions about the treatment’s risks.

The retrospective study, published in JAMA Neurology, focused on 234 patients with very mild or mild Alzheimer’s disease who received lecanemab infusions in the Memory Diagnostic Center at WashU Medicine, a clinic that specialises in treating patients with dementia.

“This new class of medications for early symptomatic Alzheimer’s is the only approved treatment that influences disease progression,” said Barbara Joy Snider, MD, PhD, a professor of neurology and co-senior author on the study. “But fear surrounding the drug’s potential side effects can lead to treatment delays. Our study shows that WashU Medicine’s outpatient clinic has the infrastructure and expertise to safely administer and care for patients on lecanemab, including the few who may experience severe side effects, leading the way for more clinics to safely administer the drug to patients.”

Lecanemab is an antibody therapy that clears amyloid plaque proteins, extending independent living by 10 months, according to a recent study led by WashU Medicine researchers. Because amyloid accumulation is the first step in the disease, doctors recommend the drug for people in the early stage of Alzheimer’s, with very mild or mild symptoms. The researchers found that only 1.8% of patients with very mild Alzheimer’s symptoms developed any adverse symptoms from treatment compared with 27% of patients with mild Alzheimer’s.

“Patients with the very mildest symptoms of Alzheimer’s will likely have the greatest benefit and the least risk of adverse events from treatment,” said Snider, who led clinical trials for lecanemab at WashU Medicine. “Hesitation and avoidance can lead patients to delay treatment, which in turn increase the risk of side effects. We hope the results help reframe the conversations between physicians and patients about the medication’s risks.”

Hesitation around lecanemab stems from a side effect known as amyloid-related imaging abnormalities, or ARIA. The abnormalities, which typically only affect a very small area of the brain, appear on brain scans and indicate swelling or bleeding. In clinical trials of lecanemab, 12.6% of participants experienced ARIA and most cases were asymptomatic and resolved without intervention. A small percentage (2.8%) experienced symptoms such as headaches, confusion, nausea and dizziness. Occasional deaths have been linked to lecanemab in an estimated 0.2% of patients treated.

The Memory Diagnostic Center began treating patients with lecanemab in 2023 after the drug received full FDA approval. Patients receive the medication via infusions every two weeks in infusion centers. As part of each patient’s care, WashU Medicine doctors regularly gather sophisticated imaging to monitor the brain, which can detect bleeding and swelling with great sensitivity. Lecanemab is discontinued in patients with symptoms from ARIA or significant ARIA without symptoms, and the rare patients with severe ARIA are treated with steroids in the hospital.

In looking back on their patients’ outcomes, the authors found the extent of side effects aligned with those of the trials – most of the clinic’s cases of ARIA were asymptomatic and only discovered on sensitive brain scans used to monitor brain changes. Of the 11 patients who experienced symptoms from ARIA, the effects largely resolved within a few months and no patients died.

“Most patients on lecanemab tolerate the drug well,” said Suzanne Schindler, MD, PhD, an associate professor of neurology and a co-senior author of the study. “This report may help patients and providers better understand the risks of treatment, which are lower in patients with very mild symptoms of Alzheimer’s.”

Source: WashU Medicine

Categories : Neurodegenerative DiseasesTags :

HIV Drugs May Offer ‘Substantial’ Alzheimer’s Protection

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

UVA Health scientists are calling for clinical trials testing the potential of HIV drugs called NRTIs to prevent Alzheimer’s disease after discovering that patients taking the drugs are substantially less likely to develop the memory-robbing condition.

The researchers, led by UVA’s Jayakrishna Ambati, MD, previously identified a possible mechanism by which the drugs could prevent Alzheimer’s. That promising finding prompted them to analyse two of the nation’s largest health insurance databases to evaluate Alzheimer’s risk among patients prescribed the medications. In one, the risk of developing Alzheimer’s decreased 6% every year the patients were taking the drugs. In the other, the annual decrease was 13%.

“It’s estimated that over 10 million people around the world develop Alzheimer’s disease annually,” said Ambati, founding director of UVA’s Center for Advanced Vision Science and the DuPont Guerry III Professor in the School of Medicine’s Department of Ophthalmology. “Our results suggest that taking these drugs could prevent approximately 1 million new cases of Alzheimer’s disease every year.”

NRTIs restrain inflammasomes

NRTIs, or nucleoside reverse transcriptase inhibitors, are used to prevent the HIV virus from replicating inside the body. But Ambati and his team previously determined that the drugs can also prevent the activation of inflammasomes, important agents of our immune system. These proteins have been implicated in the development of Alzheimer’s disease, so Ambati and his colleagues wanted to see if patients taking the inflammasome-blocking drugs were less likely to develop Alzheimer’s.

To do that, they reviewed 24 years of patient data contained in the U.S. Veterans Health Administration Database – made up heavily of men – and 14 years of data in the MarketScan database of commercially insured patients, which offers a broader representation of the population. They looked for patients who were at least 50 years old and were taking medications for either HIV or hepatitis B, another disease treated with NRTIs. They excluded patients with a previous Alzheimer’s diagnosis.

In total, the researchers identified more than 270 000 patients who met the study criteria and then analysed how many went on to develop Alzheimer’s. Even after adjusting for factors that might cloud the results, such as whether patients had pre-existing medical conditions, the researchers determined that the reduction in risk among patients on NRTIs was “significant and substantial,” they report in a new scientific paper.

The researchers note that patients taking other types of HIV medications did not show the same reduction in Alzheimer’s risk as those on NRTIs. Based on that, they say that NRTIs warrant clinical testing to determine their ability to ward off Alzheimer’s. 

If successful, the benefits could be tremendous, as Alzheimer’s rates are climbing dramatically. Nearly 7 million Americans are living with the disease today, but that number is expected to climb to 13 million by 2050. Further, the estimated annual cost of care for Alzheimer’s and other dementias could rise from $360 billion to almost $1 trillion, the Alzheimer’s Association reports.

“We have also developed a new inflammasome-blocking drug called K9, which is a safer and more effective version of NRTIs,” Ambati said. “This drug is already in clinical trials for other diseases, and we plan to also test K9 in Alzheimer’s disease.”

Source: University of Virginia Health

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Rare Congenital Paralysis Disease is Driven by Immune Cells

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Study confirmed early-stage brain inflammation in mice

Photo by Jon Tyson on Unsplash

Patients with spastic paraplegia type 15 develop movement disorders during adolescence that may ultimately require the use of a wheelchair. In the early stages of this rare hereditary disease the brain appears to play a major role by over-activating the immune system, as shown by a recent study published in the Journal of Experimental Medicine. The study was led by researchers at the University of Bonn and the German Center for Neurodegenerative Diseases (DZNE). These findings could also be relevant for Alzheimer’s disease and other neurodegenerative conditions.

Spastic paraplegia type 15 is characterised by the progressive loss of neurons in the central nervous system that are responsible for controlling movement. Initial symptoms typically appear in late childhood, manifesting first in the legs in the form of uncontrollable twitching and paralysis. “What exactly causes these neurons to die is still not fully understood,” explains Professor Elvira Mass from the LIMES Institute at the University of Bonn. “In this study, we investigated the potential role of the immune system in this process.”

Professor Mass and Dr. Marc Beyer from the DZNE, together with Professor Ralf Stumm from University Hospital Jena, served as the study’s lead investigators, bringing together extensive experience to study this rare hereditary disease. The condition is triggered by a defect in the so-called SPG15 gene, which contains instructions for building a protein. But due to that defect, the protein cannot be produced.

Severe inflammation preceding the onset of cell damage

In their experiments the researchers used mice that shared the same genetic defect. “There was existing evidence that inflammatory processes in the brain play a role in development of the disease,” Dr Beyer explains, “So we studied microglia, which are the immune cells of the brain, and also whether immune cells in bone marrow are additionally involved in the inflammatory response.”

White blood cells form in bone marrow and can reach the brain via the bloodstream. Microglia, on the other hand, have already migrated to the brain during embryonic development. The researchers succeeded in specifically labelling the cells derived from bone marrow with a fluorescent dye. “This makes them distinguishable from microglia under a microscope,” Mass elaborates. “This allowed us to study the interaction between these two cell populations at the individual cell level.”

Analyses show that the microglia cells undergo dramatic changes in very early stages of the disease, long before any neuronal damage is identifiable. The cells are thereby altered into “disease-associated microglia.” These release messenger substances which, among other things, call for the help of cytotoxic “killer” T cells from the bone marrow that destroy other cells. The two cell types communicate with each other via signaling molecules, and their interplay drives the inflammatory process.

New therapeutic possibilities

“Our data suggest that the early stages of the disease are driven not by the loss of motor neurons but rather by the severe, early immune response,” Mass relates, “and that finding implies new therapeutic possibilities. Immune suppression drugs could potentially help slow progression of the disease.”

Inflammatory processes in the brain play an important role in Alzheimer’s and other neurodegenerative diseases. Spastic paraplegia is caused by entirely different conditions than dementia, but a very similar disruption of the immune system could be involved in dementia.

Source: University of Bonn