Category: Neurodegenerative Diseases

Categories : Lab Tests and Imaging Neurodegenerative DiseasesTags :

New Pulsatility Metric in Brain Blood Vessels for Studying Dementia

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Photo by Anna Shvets on Pexels

Researchers from the Mātai Institute and the Auckland Bioengineering Institute have developed a new metric from measured blood circulation in the brain. The new metric opens up new research avenues for brain conditions, including Alzheimer’s disease and other forms of dementia. The research has been published in the leading research journal Scientific Reports Nature.

Each time the heart beats, it pumps blood through the brain vessels, causing them to expand slightly and then relax. This pulsation in the brain helps distribute blood evenly across different areas of the brain, ensuring that all parts receive the oxygen and nutrients they need to function properly.

In healthy vessels, the pulse wave is dampened before it reaches the smallest vessels, where high pulsatility could be harmful. The new metric provides a comprehensive measure of the small vessel pulsatility risk.

The new metric is based on 4D flow MRI technology, and is particularly crucial because increased vascular pulsatility is linked to several brain conditions, including Alzheimer’s disease and other forms of dementia.

By accurately measuring how pulsatility is transmitted in the brain, researchers can better understand the underlying mechanisms of these diseases and potentially guide the development of new treatments.

Current MRI methods face limitations due to anatomical variations and measurement constraints. The new technique removes this issue by integrating thousands of measurements across all brain vessels, rather than the traditional method of looking at one spot. This provides a richer metric representative of the entire brain.

“The ability to measure how pulsatility is transmitted through the brain’s arteries could revolutionise our approach to neurological diseases, and support research in vascular damage hypotheses,” says first author Sergio Dempsey.

“Our method allows for a detailed assessment of the brain’s vascular health, which is often compromised in neurodegenerative disorders.”

The study also highlighted the potential to enhance clinical assessments and research on brain health. By integrating this new metric into routine diagnostic procedures, healthcare providers can offer more precise and personalised care plans for individuals at risk of or suffering from cognitive impairments.

To make the most of the new metric’s implications for patient care, the researchers have made their tools publicly available, integrating them into pre-existing open-source software. This enables scientists and clinicians worldwide to adopt the advanced methodology, fostering further research and collaboration in the field of neurology.

Results from the initial study of the metric also identified important sex differences in vascular dynamics which has initiated a new study focusing on sex-related dynamics.

The research team is planning further studies to explore the applications of this technique in larger and more diverse populations.

Source: University of Auckland

Categories : Neurodegenerative Diseases UrologyTags :

Could Drugs for Enlarged Prostate also Protect against Lewy Body Dementia?

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Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health

A new study published in Neurology suggests that certain drugs commonly used to treat enlarged prostate may also decrease the risk for dementia with Lewy bodies (DLB). This observational finding may seem surprising, but it mirrors previous work by the University of Iowa Health Care team that links the drugs to a protective effect in another neurodegenerative condition: Parkinson’s disease. 

The UI researchers think that a specific side effect of the drugs targets a biological flaw shared by DLB and Parkinson’s disease, as well as other neurodegenerative diseases, raising the possibility that they may have broad potential for treating a wide range of neurodegenerative conditions. 

“Diseases like dementia with Lewy bodies, or Parkinson’s disease, or Alzheimer’s disease are debilitating, and we don’t really have any good treatments that can modify the disease progression. We can treat symptoms, but we can’t actually slow the disease,” explains lead study author Jacob Simmering, PhD, UI assistant professor of internal medicine. “One of the most exciting things about this study is that we find that same neuroprotective effect that we saw in Parkinson’s disease. If there is a broadly protective mechanism, these medications could potentially be used to manage or prevent other neurodegenerative diseases.” 

Large observational study links prostate drugs to lower risk of dementia with Lewy bodies

DLB is a neurodegenerative disease that causes substantial and rapid cognitive decline and dementia. It affects about one in 1000 people per year, accounting for 3 to 7% of all dementia cases. 

For the new study, the UI researchers used a large database of patient information to identify more than 643 000 men with no history of DLB who were newly starting one of six drugs used to treat benign prostatic hyperplasia (enlarged prostate). 

Three of the drugs, terazosin, doxazosin, and alfuzosin (Tz/Dz/Az), have an unexpected side effect; they can boost energy production in brain cells. Preclinical studies suggest that this ability may help slow or prevent neurodegenerative diseases like PD and DLB.  

The other drugs, tamsulosin and two 5-alpha-reductase inhibitors (5ARIs) called finasteride and dutasteride, do not enhance energy production in the brain and therefore provide a good comparison to test the effect of the Tz/Dz/Az drugs. 

The team then followed the data on these men from when they started taking the medication until they left the database or developed dementia with Lewy bodies, whichever happened first. On average, the men were followed for about three years. 

Because all the participants were selected to start a drug that treats the same condition, the researchers reasoned that the men were likely similar to each other at the outset of the treatment. The men were all propensity score-matched for characteristics like age, year of medication start, and other illnesses they had before starting the treatment, to further reduce the differences between the groups. 

“We found that men who took Tz/Az/Dz drugs were less likely to develop a diagnosis of dementia with Lewy bodies,” Simmering says. “Overall, men taking terazosin-type medications had about a 40% lower risk of developing a DLB diagnosis compared to men taking tamsulosin, and about a 37% reduction in risk compared to men taking five alpha reductase inhibitors.” 

Meanwhile, there was no statistically significant difference in risk between men taking tamsulosin and alpha reductase inhibitors. 

Approved drugs show potential

Since this was an observational study, causation cannot be established, only an association. In addition, the study only included men because the drugs are prescribed for prostate problems, which means that the researchers don’t know if the findings would apply to women. However, Simmering and his colleagues are excited by the potential of these drugs, which are already FDA approved, inexpensive, and have been used safely for decades. 

“If terazosin and these similar medications can help slow this progression – if not outright preventing the disease – this would be important to preserving cognitive function and quality of life in people with DLB,” Simmering says. 

Source: University of Iowa Carver College of Medicine

Categories : Neurodegenerative DiseasesTags :

New Ultrasound and Genetics Combination Precisely Targets Neurons in Diseased Regions

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McKelvey School of Engineering researchers have developed a noninvasive technology combining a holographic acoustic device with genetic engineering that allows them to precisely target affected neurons in the brain, creating the potential to precisely modulate selected cell types in multiple diseased brain regions. (Credit: Yaoheng Yang)

Brain diseases such as Parkinson’s disease involve damage in more than one region of the brain, requiring technology that could precisely and flexibly address all affected regions simultaneously. Researchers have developed a noninvasive technology combining a holographic acoustic device with genetic engineering that allows them to precisely target affected neurons in the brain. This has the potential to precisely modulate selected cell types in multiple diseased brain regions. 

Hong Chen, associate professor of biomedical engineering and neurosurgery at Washington University in St. Louis and her team created AhSonogenetics, or Airy-beam holographic sonogenetics, a technique that uses a noninvasive wearable ultrasound device to alter genetically selected neurons in the brains of mice. Results of the proof-of-concept study were published in Proceedings of the National Academy of Sciences. 

AhSonogenetics brings together several of Chen’s group’s recent advances into one technology. In 2021, she and her team launched Sonogenetics, a method that uses focused ultrasound to deliver a viral construct containing ultrasound-sensitive ion channels to genetically selected neurons in the brain. They use low-intensity focused ultrasound to deliver a small burst of warmth, which opens the ion channels and activates the neurons. Chen’s team was the first to show that sonogenetics could modulate the behaviour of freely moving mice.

In 2022, she and members of her lab designed and 3D-printed a flexible and versatile tool known as an Airy beam-enabled binary acoustic metasurface that allowed them to manipulate ultrasound beams. She also is developing Sonogenetics 2.0, which combines the advantage of ultrasound and genetic engineering to modulate defined neurons noninvasively and precisely in the brains of humans and animals. AhSonogenetics brings them together as a potential method to intervene in neurodegenerative diseases. 

“By enabling precise and flexible cell-type-specific neuromodulation without invasive procedures, AhSonogenetics provides a powerful tool for investigating intact neural circuits and offers promising interventions for neurological disorders,” Chen said. 

Sonogenetics gives researchers a way to precisely control the brains, while airy-beam technology allows researchers to bend or steer the sound waves to generate arbitrary beam patterns inside the brain with a high spatial resolution. Yaoheng (Mack) Yang, a postdoctoral research associate who earned a doctorate in biomedical engineering from McKelvey Engineering in 2022, said the technology gives the researchers three unique advantages.

“Airy beam is the technology that can give us precise targeting of a smaller region than conventional technology, the flexibility to steer to the targeted brain regions, and to target multiple brain regions simultaneously,” Yang said.

Chen and her team, including first authors Zhongtao Hu, a former postdoctoral research associate, and Yang, designed each Airy-beam metasurface individually as the foundation for wearable ultrasound devices that were tailored for different applications and for precise locations in the brain.

Chen’s team tested the technique on a mouse model of Parkinson’s disease. With AhSonogenetics, they were able to stimulate two brain regions simultaneously in a single mouse, eliminating the need for multiple implants or interventions. This stimulation alleviated Parkinson’s-related motor deficits in the mouse model, including slow movements, difficulty walking and freezing behaviours.

The team’s Airy-beam device overcomes some of the limits of sonogenetics, including tailoring the design of the device to target specific brain locations, as well as incorporating the flexibility to adjust target locations in a single brain.

Hu said the device, which costs roughly $50 to make, can be tailored in size to fit various brain sizes, expanding its potential applications. 

“This technology can be used as a research platform to speed neuroscience research because of the capability to flexibly target different brain regions,” Hu said. “The affordability and ease of fabrication lower the barriers to the widespread adoption of our proposed devices by the research community for neuromodulation applications.”

Source: Washington University in St. Louis

Categories : Gastrointestinal Neurodegenerative DiseasesTags :

Gut Bacteria in Parkinson’s Disease Produce Fewer B Vitamins

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In Parkinson’s disease, a reduction in the gut bacteria of genes responsible for synthesising the essential B vitamins B2 and B7 was found. Credit: Reiko Matsushita

A study led by Nagoya University in Japan has revealed a link between gut microbiota and Parkinson’s disease (PD). The researchers found that the gut bacteria genes responsible for synthesising vitamins B2 and B7 were reduced. This gene reduction was also linked to low levels of agents that help maintain the integrity of the intestinal barrier, which when weakened causes the inflammation seen in PD. Their findings, published in npj Parkinson’s Disease, suggest that treatment with B vitamins to address these deficiencies can be used to treat PD. 

PD is characterized by a variety of physical symptoms that hinder daily activities and mobility, such as shaking, slow movement, stiffness, and balance problems. While the frequency of PD may vary between different populations, it is estimated to affect approximately 1-2% of individuals aged 55 years or older. 

Various physiological processes are heavily influenced by the microorganisms found in the gut, which are collectively known as gut microbiota. In ideal conditions, gut microbiota produce SCFAs and polyamines, which maintain the intestinal barrier that prevents toxins entering the bloodstream. Toxins in the blood can be carried to the brain where they cause inflammation and affect neurotransmission processes that are critical for maintaining mental health.

To better understand the relationship between the microbial characteristics of the gut in PD, Hiroshi Nishiwaki and Jun Ueyama from the Nagoya University Graduate School of Medicine conducted a metanalysis of stool samples from patients with PD from Japan, the United States, Germany, China, and Taiwan. They used shotgun sequencing, a technique that sequences all genetic material in a sample. This is an invaluable tool because it offers researchers a better understanding of the microbial community and genetic makeup of the sample.

They observed a decrease in the bacterial genes responsible for the synthesising of riboflavin (vitamin B2) and biotin (vitamin B7) in patients diagnosed with PD. Riboflavin and biotin, derived from both food and gut microbiota, have anti-inflammatory properties, which may counteract the neuroinflammation seen in diseases like PD. 

B vitamins play crucial roles in the metabolic processes that influence the production and functions of short-chain fatty acids (SCFAs) and polyamines, two agents that help maintain the integrity of the intestinal barrier, preventing toxins entering the bloodstream. An examination of fecal metabolites revealed decreases of both in patients with PD. 

The findings indicate a potential explanation for the progression of PD. “Deficiencies in polyamines and SCFAs could lead to thinning of the intestinal mucus layer, increasing intestinal permeability, both of which have been observed in PD,” Nishiwaki explained. “This higher permeability exposes nerves to toxins, contributing to abnormal aggregation of alpha-synuclein, activating the immune cells in the brain, and leading to long-term inflammation.” 

He added, “Supplementation therapy targeting riboflavin and biotin holds promise as a potential therapeutic avenue for alleviating PD symptoms and slowing disease progression.”

The results of the study highlight the importance of understanding the complex relationship among gut microbiota, metabolic pathways, and neurodegeneration. In the coming years, customised therapy could potentially be based on patients’ unique microbiome profiles. By altering bacterial levels in the microbiome, doctors can potentially delay the onset of symptoms associated with diseases like PD.

“We could perform gut microbiota analysis on patients or conduct faecal metabolite analysis,” Nishiwaki said. “Using these findings, we could identify individuals with specific deficiencies and administer oral riboflavin and biotin supplements to those with decreased levels, potentially creating an effective treatment.”

Source: Nagoya University

The study, “Meta-analysis of shotgun sequencing of gut microbiota in Parkinson’s disease,” was published in npj Parkinson’s Disease on May 21, 2024, at DOI:10.1038/s41531-024-00724-z.

Categories : Neurodegenerative DiseasesTags :

Those with Alzheimer’s Disease History on Mother’s Side have Increased Amyloid Proteins

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

A new study by investigators from Mass General Brigham suggests that whether a person inherits risk of Alzheimer’s disease from their mother or father influences risk of biological changes in the brain that lead to disease. By evaluating 4400 cognitively unimpaired adults ages 65–85, the team found those with a history of Alzheimer’s disease (AD) on either their mother’s side or both parents’ sides had increased amyloid in their brains. Their results are published in JAMA Neurology.

“Our study found if participants had a family history on their mother’s side, a higher amyloid level was observed,” said senior corresponding author Hyun-Sik Yang, MD, a neurologist at Mass General Brigham.

Yang said that previous smaller studies have investigated the role family history plays in Alzheimer’s disease. Some of those studies suggested maternal history represented a higher risk of developing Alzheimer’s, but the group wanted to revisit the question with cognitively normal participants and access to a larger clinical trial data set.

The team examined the family history of older adults from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study, a randomized clinical trial aimed at AD prevention. Participants were asked about memory loss symptom onset of their parents. Researchers also asked if their parents were ever formally diagnosed or if there was autopsy confirmation of Alzheimer’s disease.

“Some people decide not to pursue a formal diagnosis and attribute memory loss to age, so we focused on a memory loss and dementia phenotype,” Yang said.

Researchers then compared those answers and measured amyloid in participants. They found maternal history of memory impairment at all ages and paternal history of early-onset memory impairment was associated with higher amyloid levels in the asymptomatic study participants. Researchers observed that having only a paternal history of late-onset memory impairment was not associated with higher amyloid levels.

“If your father had early onset symptoms, that is associated with elevated levels in the offspring,” said Mabel Seto, PhD, first author and a postdoctoral research fellow in the Department of Neurology at the Brigham. “However, it doesn’t matter when your mother started developing symptoms – if she did at all, it’s associated with elevated amyloid.”

Seto works on other projects related to sex differences in neurology. She said the results of the study are fascinating because Alzheimer’s tends to be more prevalent in women. “It’s really interesting from a genetic perspective to see one sex contributing something the other sex isn’t,” Seto said. She also noted the findings were not affected by whether study participants were biologically male or female.

Yang noted one limitation of the study is some participants’ parents died young, before they could potentially develop symptoms of cognitive impairment. He said social factors like access to resources and education may have also played a role in when someone acknowledged cognitive impairment and if they were ever formally diagnosed.

“It’s also important to note a majority of these participants are non-Hispanic white,” Seto added. “We might not see the same effect in other races and ethnicities.”

Seto said the next steps are to expand the study to look at other groups and examine how parental history affects cognitive decline and amyloid accumulation over time and why DNA from the mother plays a role.

Reisa Sperling, MD, a co-author on the paper, principal investigator of the A4 Study and a neurologist at Mass General Brigham, said the findings could be used soon in clinical translation.

“This work indicates that maternal inheritance of Alzheimer’s disease may be an important factor in identifying asymptomatic individuals for ongoing and future prevention trials,” Sperling said.

Source: Mass General Brigham

Categories : Neurodegenerative DiseasesTags :

Study Suggests Leprosy Drug may be Effective in Huntington’s Disease

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Source: CC0

A preclinical study from Karolinska Institutet offers hope for treating severe neurodegenerative diseases with an existing drug: clofazimine, which is used to treat leprosy, may be effective in the treatment of Huntington’s disease.

The research group examined whether existing drugs could reduce the toxicity of so-called polyQ proteins. These proteins are found in patients with certain hereditary neurodegenerative diseases, including Huntington’s disease, for which there is no cure. 

Screening hundreds of drugs, they found that the leprosy drug clofazimine reduces the toxicity of polyQ proteins and restores mitochondrial function in zebrafish and worms. The finding, published in eBioMedicine, supports the previous hypothesis that polyQ diseases are associated with the dysfunction of mitochondria, the organelles in charge of producing energy within cells.

“Our work not only suggests the interest of a specific drug for the treatment of polyQ neurodegenerative diseases, but also helps us to better understand what causes these diseases. It is possible to find new uses for old drugs, which reduces the time needed to find novel therapies”, says last author Oscar Fernandez-Capetillo, Professor and research group leader at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.

Clofazimine is not very efficient in entering the nervous system, however. The research group are now trying to figure out solutions to this limitation, by testing the efficacy of clofazimine in mammalian models of neurodegenerative disease. 

“We hope that our discovery can be developed into a new medicine, but there are still some hurdles that need to be overcome,” says Oscar Fernandez-Capetillo.

The researchers are also conducting similar drug screens in other age-related pathologies such as cancer and other neurodegenerative disorders.

Source: Karolinska Institutet

Categories : Neurodegenerative Diseases NeurologyTags :

In Alzheimer’s, Bungled Instructions are Carried between Neurons

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

In findings published in Cell Reports, researchers discovered that the biological instructions within vesicles that communicate between cells differed significantly in postmortem brain samples donated from patients suffering from Alzheimer’s disease.

Small extracellular vesicles (sEVs) are tiny containers are produced by most cells in the body to ferry a wide variety of proteins, lipids and byproducts of cellular metabolism, as well as RNA nucleic acid codes used by recipient cells to construct new proteins.

Because this biologically active cargo can easily elicit changes in other cells, scientists are interested in brain sEVs as a medium for passing along normal as well as bungled instructions for misfolded proteins that accumulate in the brain as neurodegenerative diseases such as Alzheimer’s disease progress.

To be a potential contributor to the buildup of unwanted proteins, sEVs would have to carry blueprints with sufficient information to enable other cells to produce the problematic proteins. Most previous research had indicated that the messenger RNA (mRNA) carrying plans for proteins were chopped into too many shorter fragments to allow recipient cells to change their construction patterns.

“We found quite the opposite to be true in our study,” says senior author Jerold Chun, MD, PhD, professor in the Center for Genetic Disorders and Aging Research at Sanford Burnham Prebys. “We identified more than 10 000 full-length mRNAs through the use of a relatively newer DNA sequencing technique called PacBio long-read sequencing.”

The team isolated sEVs from the prefrontal cortex of 12 postmortem brain samples donated from patients diagnosed with Alzheimer’s disease and 12 from donors without Alzheimer’s disease (or any other known neurological disease). Nearly 80% of identified mRNAs were full-length, allowing them to be transcribed by recipient cells into viable proteins.

“To corroborate the results of long-read sequencing in the human samples, we also looked at vesicles isolated from mouse cells,” says first author Linnea Ransom, PhD, postdoctoral fellow. “We found similar averages of between 78% and 86% full-length transcripts in three brain cell types: astrocytes, microglia and neurons.”

The researchers also compared the sequence of genes reflected in the sEV mRNA transcriptome. In Alzheimer’s disease samples, 700 genes showed increased expression whereas nearly 1500 were found to have reduced activity.

The scientists determined that the 700 upregulated genes are associated with inflammation and immune system activation, which fits within known patterns of brain inflammation present in neurodegenerative diseases such as Alzheimer’s disease. The researchers also found many genes associated with Alzheimer’s disease in prior genome-wide association studies also were present in Alzheimer’s disease sEVs.

“The changes in gene expression contained in these vesicles reveal an inflammatory signature that may serve as a window into disease processes occurring in the brain as Alzheimer’s disease progresses,” says Chun.

Following this study, Chun and team will dig deeper into how cells package sEVs and how the enclosed mRNA codes lead to functional changes in other brain cells affected in Alzheimer’s disease. Better understanding of sEVs and their mRNA contents may enable the discovery of biomarkers that could be used to improve early detection of Alzheimer’s disease and potentially other neurological conditions, while identifying new disease mechanisms to provide new therapeutic targets.

“Additionally, sEVs naturally occur as a vehicle for transporting biologically active cargo between cells, so it also may be possible to leverage them as a targeted delivery system for future brain therapies” says Chun.

Source: Sanford-Burnham Prebys

Categories : Environmental Effects Neurodegenerative DiseasesTags :

Risk Factors for Faster Aging in the Brain Revealed in New Study

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Source: CC0

Researchers from the Nuffield Department of Clinical Neurosciences at the University of Oxford have used data from UK Biobank participants to reveal that diabetes, traffic-related air pollution and alcohol intake are the most harmful out of 15 modifiable risk factors for dementia.

The researchers had previously identified a ‘weak spot’ in the brain, which is a specific network of higher-order regions that not only develop later during adolescence, but also show earlier degeneration in old age.

They showed that this brain network is also particularly vulnerable to schizophrenia and Alzheimer’s disease.

In this new study, published in Nature Communications, they investigated the genetic and modifiable influences on these fragile brain regions by looking at the brain scans of 40 000 UK Biobank participants aged over 45.

The researchers examined 161 risk factors for dementia, and ranked their impact on this vulnerable brain network, over and above the natural effects of age.

They classified these modifiable risk factors into 15 broad categories: blood pressure, cholesterol, diabetes, weight, alcohol consumption, smoking, depressive mood, inflammation, pollution, hearing, sleep, socialisation, diet, physical activity, and education.

Prof Gwenaëlle Douaud, who led this study, said: “We know that a constellation of brain regions degenerates earlier in aging, and in this new study we have shown that these specific parts of the brain are most vulnerable to diabetes, traffic-related air pollution – increasingly a major player in dementia – and alcohol, of all the common risk factors for dementia.”

“We have found that several variations in the genome influence this brain network, and they are implicated in cardiovascular deaths, schizophrenia, Alzheimer’s and Parkinson’s diseases, as well as with the two antigens of a little-known blood group, the elusive XG antigen system, which was an entirely new and unexpected finding.”

Prof Lloyd Elliott, a co-author from Simon Fraser University in Canada, concurs: ‘In fact, two of our seven genetic findings are located in this particular region containing the genes of the XG blood group, and that region is highly atypical because it is shared by both X and Y sex chromosomes.

This is really quite intriguing as we do not know much about these parts of the genome; our work shows there is benefit in exploring further this genetic terra incognita.’

Importantly, as Prof Anderson Winkler, a co-author from the National Institutes of Health and The University of Texas Rio Grande Valley in the US, points out: “What makes this study special is that we examined the unique contribution of each modifiable risk factor by looking at all of them together to assess the resulting degeneration of this particular brain ‘weak spot’. It is with this kind of comprehensive, holistic approach – and once we had taken into account the effects of age and sex – that three emerged as the most harmful: diabetes, air pollution, and alcohol.”

This research sheds light on some of the most critical risk factors for dementia, and provides novel information that can contribute to prevention and future strategies for targeted intervention.

Source: University of Oxford

Categories : Neurodegenerative Diseases TransplantsTags :

Familial Alzheimer’s Disease Transferred via Bone Marrow Transplant in Mice Experiment

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Photo by Mari Lezhava on Unsplash

Familial Alzheimer’s disease can be transferred via bone marrow transplant, researchers show in the journal Stem Cell Reports. When the team transplanted bone marrow stem cells from mice carrying a hereditary version of Alzheimer’s disease into normal lab mice, the recipients developed Alzheimer’s disease – and at an accelerated rate.

The study highlights the role of amyloid that originates outside of the brain in the development of Alzheimer’s disease, which changes the paradigm of Alzheimer’s from being a disease that is exclusively produced in the brain to a more systemic disease. Based on their findings, the researchers say that donors of blood, tissue, organ, and stem cells should be screened for Alzheimer’s disease to prevent its inadvertent transfer during blood product transfusions and cellular therapies.

“This supports the idea that Alzheimer’s is a systemic disease where amyloids that are expressed outside of the brain contribute to central nervous system pathology,” says senior author and immunologist Wilfred Jefferies, of the University of British Columbia. “As we continue to explore this mechanism, Alzheimer’s disease may be the tip of the iceberg and we need to have far better controls and screening of the donors used in blood, organ and tissue transplants as well as in the transfers of human derived stem cells or blood products.”

To test whether a peripheral source of amyloid could contribute to the development of Alzheimer’s in the brain, the researchers transplanted bone marrow containing stem cells from mice carrying a familial version of the disease — a variant of the human amyloid precursor protein (APP) gene, which, when cleaved, misfolded and aggregated, forms the amyloid plaques that are a hallmark of Alzheimer’s disease. They performed transplants into two different strains of recipient mice: APP-knockout mice that lacked an APP gene altogether, and mice that carried a normal APP gene.

In this model of heritable Alzheimer’s disease, mice usually begin developing plaques at 9 to 10 months of age, and behavioural signs of cognitive decline begin to appear at 11 to 12 months of age. Surprisingly, the transplant recipients began showing symptoms of cognitive decline much earlier – at 6 months post-transplant for the APP-knockout mice and at 9 months for the “normal” mice.

“The fact that we could see significant behavioural differences and cognitive decline in the APP-knockouts at 6 months was surprising but also intriguing because it just showed the appearance of the disease that was being accelerated after being transferred,” says first author Chaahat Singh of the University of British Columbia.

In mice, signs of cognitive decline present as an absence of normal fear and a loss of short and long-term memory. Both groups of recipient mice also showed clear molecular and cellular hallmarks of Alzheimer’s disease, including leaky blood-brain barriers and buildup of amyloid in the brain.

Observing the transfer of disease in APP-knockout mice that lacked an APP gene altogether, the team concluded that the mutated gene in the donor cells can cause the disease and observing that recipient animals that carried a normal APP gene are susceptible to the disease suggests that the disease can be transferred to health individuals.

Because the transplanted stem cells were hematopoietic cells, meaning that they could develop into blood and immune cells but not neurons, the researchers’ demonstration of amyloid in the brains of APP knockout mice shows definitively that Alzheimer’s disease can result from amyloid that is produced outside of the central nervous system.

Finally the source of the disease in mice is a human APP gene demonstrating the mutated human gene can transfer the disease in a different species.

In future studies, the researchers plan to test whether transplanting tissues from normal mice to mice with familial Alzheimer’s could mitigate the disease and to test whether the disease is also transferable via other types of transplants or transfusions and to expand the investigation of the transfer of disease between species.

“In this study, we examined bone marrow and stem cells transplantation. However, next it will be important to examine if inadvertent transmission of disease takes place during the application of other forms of cellular therapies, as well as to directly examine the transfer of disease from contaminated sources, independent from cellular mechanisms,” says Jefferies.

Source: Cell Press

Categories : Neurodegenerative DiseasesTags :

Difficulty in Navigating could Predict Alzheimer’s Years Before Symptom Onset

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People at risk of Alzheimer’s disease have impaired spatial navigation before they develop problems with other cognitive functions, including memory, finds a new study led by UCL researchers.

The research, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, used virtual reality to test the spatial navigation of 100 asymptomatic midlife adults, aged 43-66, from the PREVENT-Dementia prospective cohort study.

Participants had a hereditary or physiological risk of Alzheimer’s disease, due to either a gene (the APOE-ε4 allele) that puts them at risk of the condition, a family history of Alzheimer’s disease, or lifestyle risk factors such as low levels of physical activity. Crucially, these participants were around 25 years younger than their estimated age of dementia onset.

Led by Professor Dennis Chan, the study used a test designed by Dr Andrea Castegnaro and Professor Neil Burgess (all UCL Institute of Cognitive Neuroscience), in which participants were asked to navigate within a virtual environment while wearing VR headsets.

The researchers found that people at greater risk of developing Alzheimer’s disease, regardless of risk factor, were selectively impaired on the VR navigation task, without a corresponding impairment on other cognitive tests. The authors say their findings suggest that impairments in spatial navigation may begin to develop years, or even decades, before the onset of any other symptoms.

First author, Dr Coco Newton (UCL Institute of Cognitive Neuroscience), who carried out the work while at University of Cambridge said: “Our results indicated that this type of navigation behaviour change might represent the very earliest diagnostic signal in the Alzheimer’s disease continuum — when people move from being unimpaired to showing manifestation of the disease.”

The researchers also found that there was a strong gender difference in how participants performed, with the impairment being observed in men and not women.

Dr Newton added: “We are now taking these findings forward to develop a diagnostic clinical decision support tool for the NHS in the coming years, which is a completely new way of approaching diagnostics and will hopefully help people to get a more timely and accurate diagnosis.

“This is particularly important with the emergence of anti-amyloid treatments for Alzheimer’s, which are considered to be most effective in the earliest stages of the disease.

“It also highlights the need for further study of the differing vulnerability of men and women to Alzheimer’s disease and the importance of taking gender into account for both diagnosis and future treatment.”

Professor Chan said: “We are excited by these findings for two main reasons. First, they improve detection of the clinical onset of Alzheimer’s disease, critical for prompt application of treatments.

“Second, the VR navigation test is based on our knowledge of the spatial properties of cells in the brain’s temporal lobe, and the application of cellular neuroscience to clinical populations helps bridge the gap in understanding how disease at the neuronal level can result in the clinical manifestation of disease. This knowledge gap currently represents one of the biggest barriers to progress in Alzheimer’s research.”

Source: University College London