Category: Neurodegenerative Diseases

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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

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

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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

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

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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

Categories : Ageing Neurodegenerative DiseasesTags :

Did the Ancient Greeks and Romans Suffer from Dementia?

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Bust of Hippocrates. By ESM – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=90175388

Age-related dementia is often assumed to having been with us all along, stretching back to the ancient world. But a new analysis of classical Greek and Roman medical texts suggests that it was extremely rare 2000 to 2500 years ago, in the time of Aristotle, Galen and Pliny the Elder.

The USC-led research, published in the Journal of Alzheimer’s Disease, bolsters the idea that Alzheimer’s disease and related dementias are diseases of modern environments and lifestyles, with sedentary behaviour and exposure to air pollution largely to blame.

“The ancient Greeks had very, very few – but we found them – mentions of something that would be like mild cognitive impairment,” said first author Caleb Finch, a University Professor at the USC Leonard Davis School of Gerontology.

“When we got to the Romans, and we uncovered at least four statements that suggest rare cases of advanced dementia – we can’t tell if it’s Alzheimer’s. So, there was a progression going from the ancient Greeks to the Romans.”

Ancient Greeks recognised that aging commonly brought memory issues that we would recognise as mild cognitive impairment, but nothing approaching a major loss of memory, speech and reasoning as caused by Alzheimer’s and other types of dementia.

Finch and co-author Stanley Burstein, a historian at California State University, Los Angeles, pored over a major body of ancient medical writing by Hippocrates and his followers.

The text catalogues ailments of the elderly such as deafness, dizziness and digestive disorders – but makes no mention of memory loss.

Centuries later in ancient Rome, a few mentions crop up. Galen remarks that at the age of 80, some elderly begin to have difficulty learning new things.

Pliny the Elder notes that the senator and famous orator Valerius Messalla Corvinus forgot his own name.

Cicero prudently observed that “elderly silliness … is characteristic of irresponsible old men, but not of all old men.”

Finch speculates that as Roman cities grew denser, pollution increased, driving up cases of cognitive decline.

In addition, Roman aristocrats used lead cooking vessels, lead water pipes and even added lead acetate into their wine to sweeten it – unwittingly poisoning themselves with the powerful neurotoxin.

(A few ancient writers recognised the toxicity of lead-containing material, but little progress was made in dealing with the problem until well into the 20th century. Some scholars blame lead poisoning for the fall of the Roman Empire.)

For this paper, Finch did not just think about the Roman Empire or the Greeks.

In the absence of demographic data for ancient Greece and Rome, Finch turned to a surprising model for ancient aging: today’s Tsimane Amerindians, an Indigenous people of the Bolivian Amazon.

The Tsimane, like the ancient Greeks and Romans, have a preindustrial lifestyle that is very physically active, and they have extremely low rates of dementia.

An international team of cognitive researchers led by Margaret Gatz, a professor of psychology, gerontology and preventive medicine at the USC Leonard Davis School, found among older Tsimane people, only about 1% suffer from dementia.

In contrast, 11% of people aged 65 and older living in the United States have dementia, according to the Alzheimer’s Association.

“The Tsimane data, which is quite deep, is very valuable,” Finch said.

“This is the best-documented large population of older people that have minimal dementia, all of which indicates that the environment is a huge determinant on dementia risk. They give us a template for asking these questions.”

Source: University of Southern California

Categories : Neurodegenerative DiseasesTags :

Alzheimer’s Disease Cases Caused by Growth Hormone Treatment

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

Five cases of Alzheimer’s are believed to have arisen as a result of medical treatments decades earlier, according to a new paper published in Nature Medicine. Alzheimer’s disease is caused by the amyloid-beta protein, and is usually a sporadic condition of late adult life, or more rarely as an inherited condition from a faulty gene.

The study, by a team of UCL and UCLH researchers, provides the first evidence of Alzheimer’s disease in living people that appears to have been medically acquired and due to transmission of the amyloid-beta protein.

The people described in the paper had all been treated as children with a type of human growth hormone extracted from pituitary glands from deceased individuals (cadaver-derived human growth hormone or c-hGH). This was used to treat at least 1848 people in the UK between 1959 and 1985, and used for various causes of short stature.

It was withdrawn in 1985 after it was recognised that some c-hGH batches were contaminated with prions (infectious proteins) which had caused Creutzfeldt-Jakob disease (CJD) in some people.

c-hGH was then replaced with synthetic growth hormone that did not carry the risk of transmitting CJD.

These researchers previously reported that some patients with CJD due to c-hGH treatment (called iatrogenic CJD) also had prematurely developed deposits of the amyloid-beta protein in their brains.* The scientists went on to show in a 2018 paper that archived samples of c-hGH were contaminated with amyloid-beta protein and, despite having been stored for decades, transmitted amyloid-beta pathology to laboratory mice when it was injected.

They suggested that individuals exposed to contaminated c-hGH, who did not succumb to CJD and lived longer, might eventually develop Alzheimer’s disease.

This latest paper reports on eight people referred to UCLH’s National Prion Clinic at the National Hospital for Neurology and Neurosurgery in London, who had all been treated with c-hGH in childhood, often over several years.

Five of these people had symptoms of dementia, and either had already been diagnosed with Alzheimer’s disease or would otherwise meet the diagnostic criteria for this condition; another person met criteria for mild cognitive impairment. These people were between 38 and 55 years old when neurological symptoms started. Biomarker analyses supported the diagnoses of Alzheimer’s disease in two patients with the diagnosis, and was suggestive of Alzheimer’s in one other person; an autopsy analysis showed Alzheimer’s pathology in another patient.

The unusually young age at which these patients developed symptoms suggests they did not have the usual sporadic Alzheimer’s which is associated with old age. In the five patients in whom samples were available for genetic testing, the team ruled out inherited Alzheimer’s disease.

As c-hGH treatment is no longer used, there is no risk of any new transmission via this route. There have been no reported cases of Alzheimer’s acquired from any other medical or surgical procedures. There is no suggestion that amyloid-beta can be passed on in day-to-day life or during routine medical or social care.

However, the researchers caution that their findings highlight the importance of reviewing measures to ensure there is no risk of accidental transmission of amyloid-beta via other medical or surgical procedures which have been implicated in accidental transmission of CJD.

The lead author of the research, Professor John Collinge, Director of the UCL Institute of Prion Diseases and a consultant neurologist at UCLH, said: “There is no suggestion whatsoever that Alzheimer’s disease can be transmitted between individuals during activities of daily life or routine medical care. The patients we have described were given a specific and long-discontinued medical treatment which involved injecting patients with material now known to have been contaminated with disease-related proteins.

“However, the recognition of transmission of amyloid-beta pathology in these rare situations should lead us to review measures to prevent accidental transmission via other medical or surgical procedures, in order to prevent such cases occurring in future.

“Importantly, our findings also suggest that Alzheimer’s and some other neurological conditions share similar disease processes to CJD, and this may have important implications for understanding and treating Alzheimer’s disease in the future.”

Source: University College London

Categories : Neurodegenerative DiseasesTags :

Crafting a ‘Key’ to Cross the Blood-brain Boundary

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Researchers led by Michael Mitchell of the University of Pennsylvania are close to gaining access through the blood-brain barrier, a long-standing boundary in biology, by granting molecules a special ‘key’ to gain access.

Their findings, published in the journal Nano Letters, present a model that uses lipid nanoparticles (LNPs) to deliver mRNA, offering new hope for treating conditions like Alzheimer’s disease and seizures.

“Our model performed better at crossing the blood-brain barrier than others and helped us identify organ-specific particles that we later validated in future models,” says Mitchell, associate professor of bioengineering at Penn’s School of Engineering and Applied Science, and senior author on the study.

“It’s an exciting proof of concept that will no doubt inform novel approaches to treating conditions like traumatic brain injury, stroke, and Alzheimer’s.”

Search for the key

To develop the model, Emily Han, a PhD candidate and NSF Graduate Research Fellow in the Mitchell Lab and first author of the paper, explains that it started with a search for the right in vitro screening platform, saying, “I was combing through the literature, most of the platforms I found were limited to a regular 96-well plate, a two-dimensional array that can’t represent both the upper and lower parts of the blood-brain barrier, which correspond to the blood and brain, respectively.”

Han then explored high-throughput transwell systems with both compartments but found they didn’t account for mRNA transfection of the cells, revealing a gap in the development process.

This led her to create a platform capable of measuring mRNA transport from the blood compartment to the brain, as well as transfection of various brain cell types including endothelial cells and neurons.

“I spent months figuring out the optimal conditions for this new in vitro system, including which cell growth conditions and fluorescent reporters to use,” Han explains.

“Once robust, we screened our library of LNPs and tested them on animal models. Seeing the brains express protein as a result of the mRNA we delivered was thrilling and confirmed we were on the right track.”

The team’s platform is poised to significantly advance treatments for neurological disorders.

It’s currently tailored for testing a range of LNPs with brain-targeted peptides, antibodies, and various lipid compositions.

However, it could also deliver other therapeutic agents like siRNA, DNA, proteins, or small molecule drugs directly to the brain after intravenous administration.

What’s more, this approach isn’t limited to the blood-brain barrier as it shows promise for exploring treatments for pregnancy-related diseases by targeting the blood-placental barrier, and for retinal diseases focusing on the blood-retinal barrier.

Next Steps

The team is eager to use this platform to screen new designs and test their effectiveness in different animal models.

They are particularly interested in working with collaborators with advanced animal models of neurological disorders.

“We’re collaborating with researchers at Penn to establish brain disease models,” Han says.

“We’re examining how these LNPs impact mice with various brain conditions, ranging from glioblastoma to traumatic brain injuries. We hope to make inroads towards repairing the blood-brain barrier or target neurons damaged post-injury.”

Source: University of Pennsylvania

Categories : Ageing Neurodegenerative DiseasesTags :

Could Bizarre Visual Symptoms Be a Telltale Sign of Alzheimer’s?

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Photo by Mari Lezhava on Unsplash

A team of international researchers, led by UC San Francisco, has completed the first large-scale study of posterior cortical atrophy, a baffling constellation of visuospatial symptoms that present as the first signs of Alzheimer’s disease. These symptoms occur in up to 10% of cases of Alzheimer’s disease.

The study, which appears in The Lancet Neurology,  includes data from more than 1000 patients at 36 sites in 16 countries.

Posterior cortical atrophy (PCA) overwhelmingly predicts Alzheimer’s, the researchers found. Some 94% of the PCA patients had Alzheimer’s pathology and the remaining 6% had conditions like Lewy body disease and frontotemporal lobar degeneration. In contrast, other studies show that 70% of patients with memory loss have Alzheimer’s pathology.

Unlike memory issues, patients with PCA struggle with judging distances, distinguishing between moving and stationary objects and completing tasks like writing and retrieving a dropped item despite a normal eye exam, said co-first author Marianne Chapleau, PhD, of the UCSF Department of Neurology, the Memory and Aging Center and the Weill Institute for Neurosciences.

Most patients with PCA have normal cognition early on, but by the time of their first diagnostic visit, an average 3.8 years after symptom onset, mild or moderate dementia was apparent with deficits identified in memory, executive function, behaviour, and speech and language, according to the researchers’ findings.

At the time of diagnosis, 61% demonstrated “constructional dyspraxia,” an inability to copy or construct basic diagrams or figures; 49% had a “space perception deficit,” difficulties identifying the location of something they saw; and 48% had “simultanagnosia,” an inability to visually perceive more than one object at a time. Additionally, 47% faced new challenges with basic math calculations and 43% with reading.

We need better tools and training to identify patients

“We need more awareness of PCA so that it can be flagged by clinicians,” said Chapleau. “Most patients see their optometrist when they start experiencing visual symptoms and may be referred to an ophthalmologist who may also fail to recognise PCA,” she said. “We need better tools in clinical settings to identify these patients early on and get them treatment.”

The average age of symptom onset of PCA is 59, several years younger than the typical memory symptoms of Alzheimer’s. This is another reason why patients with PCA are less likely to be diagnosed, Chapleau added.

Early identification of PCA may have important implications for Alzheimer’s treatment, said co-first author Renaud La Joie, PhD, also of the UCSF Department of Neurology and the Memory and Aging Center. In the study, levels of amyloid and tau, identified in cerebrospinal fluid and imaging, as well as autopsy data, matched those found in typical Alzheimer’s cases. As a result, patients with PCA may be candidates for anti-amyloid therapies, like lecanemab (Leqembi), approved by the U.S Food and Drug Administration in January 2023, and anti-tau therapies, currently in clinical trials, both of which are believed to be more effective in the earliest phases of the disease, he said.

“Patients with PCA have more tau pathology in the posterior parts of the brain, involved in the processing of visuospatial information, compared to those with other presentations of Alzheimer’s. This might make them better suited to anti-tau therapies,” he said.

Patients have mostly been excluded from trials, since they are “usually aimed at patients with amnestic Alzheimer’s with low scores on memory tests,” La Joie added. “However, at UCSF we are considering treatments for patients with PCA and other non-amnestic variants.”

Better understanding of PCA is “crucial for advancing both patient care and for understanding the processes that drive Alzheimer’s disease,” said senior author Gil Rabinovici, MD, director of the UCSF Alzheimer’s Disease Research Center. “It’s critical that doctors learn to recognise the syndrome so patients can receive the correct diagnosis, counseling and care.

“From a scientific point of view, we really need to understand why Alzheimer’s is specifically targeting visual rather than memory areas of the brain. Our study found that 60% of patients with PCA were women – better understanding of why they appear to be more susceptible is one important area of future research.”

Source: University of California San Francisco