Background

Having specific genes and lifestyles can increase the chances of developing dementia. Because changes to the brain happen years before people show symptoms of dementia, it is important to study brain changes related to dementia as early as possible. This leads researchers to sometimes look at relatively young individuals and search for any dementia-related signs in those who have risk factors. For example, previous research found that people with specific Alzheimer’s disease-related genes have a different shape of some brain areas than people without these genes

The authors propose that oestradiol causes autophagy which promotes clearing of tau in nerve cells. The study aims to investigate how oestradiol may regulate autophagy and how this may be used as a possible strategy for treating or preventing the disease. 

What did the authors do and how did they do it? 

Currently, it is not possible to cure dementia, but some scientific studies show that preventing, or at least delaying, its start is possible. This can be done by some lifestyle changes that could eliminate risk factors such as smoking or having an unhealthy weight. By making those changes we not only take care of our physical health, but we also take care of our brain health. This could potentially also help with reducing the chances of developing dementia. But other elements also contribute to the chances of developing dementia, for example specific genes. Finding the potential relationship between those lifestyle changes and genes and how this relationship translates to brain-related changes is crucial in finding a key to preventing dementia.

What are the results? 

The authors took information from the UK Biobank, which is the biggest database containing health care information and brain scans in the UK. In this study, they investigated the relationship between the lifestyle, brain structure and genes of 25,894 individuals aged 37 to 73 years. 

At first, they focused on lifestyle factors. They looked at the habits of individuals such as smoking, diet, meat intake, alcohol consumption, regular physical activity and so on. Taking all this information together, they created an indicator of how healthy the lifestyle of each person was. Then, they did the same for a genetic combination of each person, which served as an indicator of genetic risks of developing Alzheimer’s Disease. 

After obtaining both indicators – of participants’ healthy lifestyle and of participants’ genetic risk, the authors compared those indicators with the brain structure. This was done to find any potential relationship between lifestyle, genes, and brain shape.

What are the results? 

The results showed that people aged over 60 who had a higher genetic risk of developing Alzheimer’s had changes in the brain structures. People below the age of 60 did not show these changes to brain sizes and shapes regardless of their genetic risk. There was also a positive relationship between a healthy lifestyle and brain changes across all ages and genetic risk groups. This shows that a healthy lifestyle can play a role as a protection, not only for our physical health, but also for our brain health. Such protection is very important for every person regardless of their potential risk of developing dementia.

What do the findings mean going forward for people with the disease?

This study does not target people already living with dementia. Instead, it focuses on people who might have a potential risk of developing dementia later in their lives. It does so by studying links between lifestyle, genetic risk factors of Alzheimer’s Disease, and brain changes. This is extremely important in preventative efforts. That is because when we talk about a healthy lifestyle, we often tend to only think about our physical fitness and health. This study shows that a healthy lifestyle can help with the protection of the brain as well. 

Author

Summary by Ludmila Kucikova, reviewed by Dr Jon Wood and a dementia lay panel

Original Paper

https://doi.org/10.3390/nu14193907

Background

Alzheimer’s Disease is an ageing-related disease that causes damage to nerve cells, leading to problems with movement, memory, and behaviour. The disease affects more woman than men, with evidence suggesting that treatment with oestradiol (a form of the hormone oestrogen) reduces memory loss in menopausal women.

Proteins are the building blocks of cells, each with specific functions to keep cells working properly. In Alzheimer’s Disease there is a build-up of a protein called tau which is toxic to nerve cells and leads to development of the disease. There are different forms of tau that a person can have based on their genetics, with some of these forms being more harmful and disease-causing than others. 

Cells have a recycling process called autophagy which breaks down harmful debris, such as damaged proteins, and recycles them into materials the cells can use. Scientists suggest that if we can control this recycling process, it could be used to clear the build-up of tau protein, as a potential treatment for Alzheimer’s Disease. 

Why is the study important? 

The authors propose that oestradiol causes autophagy which promotes clearing of tau in nerve cells. The study aims to investigate how oestradiol may regulate autophagy and how this may be used as a possible strategy for treating or preventing the disease. 

What did the authors do and how did they do it? 

To investigate how oestradiol may cause the autophagy process to clear tau build-up, the authors used nerve like cells grown in a dish with either no tau build-up, build-up of normal tau (found in most people with Alzheimer’s disease) or build-up of a more harmful form of tau (found only in some people with Alzheimer’s disease). They applied oestradiol to the cells and measured how much autophagy occurred and how much of the tau was cleared from the cells. 

What are the results? 

The authors found that in cells with no tau build-up or with build-up of normal tau, applying oestradiol caused an increase in autophagy and increased the amount of tau build up cleared from the cells. However, they found that applying oestradiol to cells with the more harmful form of tau build up did not cause an increase in autophagy or an increase in the amount of tau cleared form the cell.

What do the finding mean going forward for people with the disease?

This study shows that oestradiol clears normal tau build-up in nerve like cells, suggesting that oestradiol may be a potential therapy for both men and women living with Alzheimer’s Disease. However, the study also shows that oestradiol does not work on all forms of tau, such as the more harmful form, so may not work for all people living with Alzheimer’s Disease. More research would help us understand if oestradiol can protect against Alzheimer’s Disease and if loss of oestradiol causes greater risk to women to develop the disease. 

Author

Summary by Natalie Pye, reviewed by Dr Ryan West and a dementia lay panel

Original Paper

https://doi.org/10.1016/j.brainres.2022.148079 

Background: 

There are many diseases, such as Alzheimer’s Disease, that cause damage to or loss of cells in our brain, leading to problems with our movement, thinking and behaviour. Recent studies have suggested there may be a link between our brain and our gut microbiota – the collection of bacteria and fungi in our gut which influences our metabolism, immune system, and other important bodily functions. Scientists think that chemicals in our body that are formed by our gut microbiota may lead to risk of diseases such as Alzheimer’s Disease, however there is not enough data to know how or why this may happen.

Why is the study important? 

The aim of this study was to investigate if there were differences in the gut microbiota and the chemicals they produce in people with Alzheimer’s Disease or healthy controls. By investigating the changes in our gut microbiota, scientists can find potential targets for treatments or markers of disease to help with diagnosis. 

What did the authors do and how did they do it? 

For this study the authors used 3 existing data sets including a study of differences in gut microbiota in 18,340 people, a study of differences in chemicals produced by the gut microbiota in 7,824 people and a study of genetic differences between 17,008 people with Alzheimer’s Disease and 37,154 healthy controls.

The authors compared the 3 data to sets to determine links in changes in gut microbiota and the chemicals they produce between healthy individuals and people living with Alzheimer’s Disease. 

What are the results? 

The authors reported increases in 3 gut microbiota bacteria that may be associated with increased risk of Alzheimer’s Disease. The study also suggested an increase in a bacterium that may be associated with decreased risk of Alzheimer’s Disease and an increase in a bacterium that may be protective against Alzheimer’s Disease. Lastly, they reported that increases in 2 chemicals produced by the gut microbiota may be protective against Alzheimer’s Disease.

What do the finding mean going forward for people with the disease?

This study further suggests a link between changes in our gut and brain in Alzheimer’s Disease and highlights some potential targets for future research into treatments or interventions, such as eating a Mediterranean diet. 

Author

Natalie Pye

Original Paper

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad215411

Background:

Games and digital tools are becoming very popular in the health sector for diagnosis, prevention, awareness, training or rehabilitation. Some of those tools that monitor our daily routine are already common. Some of us might have watches that monitor our heart rate or physical activity and tell us when to move for a little bit. Or our phones can track how many steps we do in a day and remind us to do some exercise. Some of us might play games on our phones that are calming and help to relieve anxiety.

Games can offer an insight into how people behave and provide researchers with easily accessible data from real life. They are available as smart devices or on computers and can be accessed when it is suitable for patients. Some of such games have the potential to distinguish early changes related to some disorders, for example, dementia.

Why is the study important?

Early identification of Alzheimer’s Disease offers opportunities to treat its symptoms before the disorder damages the brain too much. If the brain is damaged too much, treatments become ineffective, and damages are irreversible. Many ways to identify Alzheimer’s Disease that are used in clinical practices nowadays are not sensitive enough for early changes related to the disorder. Therefore, researchers are constantly trying to find new ways of identifying Alzheimer’s Disease earlier to increase the chances of successful treatment. In this study, the authors are trying to find a way to identify Alzheimer’s Disease by using a game.

What did the authors do and how did they do it?

The authors designed a game called AlzCoGame which aims to monitor a range of functions in older people. This game allows users to train specific kinds of memory that are linked with Alzheimer’s Disease, as well as other functions such as their concentration or attention. All games are based on virtual scenarios that occur in daily lives, for example, a shopping task or a cooking task.

While users engage in a game, their data are collected and used for statistical analysis. This analysis is based on artificial intelligence which can predict whether users might develop Alzheimer’s Disease based on their performance in a game. The researchers test several artificial intelligence methods to see which one is the most accurate.

What are the results?

The results revealed that data collected from the game could identify early stages of Alzheimer’s Disease with 83-92% accuracy depending on what artificial intelligence method was used for the analysis. Based on these encouraging results, the authors recommend this game to be included in clinical trials. This means that more patients would test how useful this tool is and whether it could be used in standard clinical practices.

What do the findings mean going forward for people with the disease?

Using games is increasingly popular among healthcare workers. Such games offer a tool to engage patients, while also gaining data for researchers to learn more about disorders. With games based on real-life scenarios, researchers and clinicians could identify key problems in day-to-day living directly and accurately. Patients in the early stages of the disorder could also use the game to continue engaging in activities that are increasingly difficult to do in a real life like shopping or cooking.

Author

Ludmila Kucikova

Original Paper

Machine learning and Serious Game for the Early Diagnosis of Alzheimer’s Disease - Samiha Mezrar, Fatima Bendella, 2022 (sagepub.com) 

Background 

Early-onset Alzheimer’s Disease (EOAD) is a form of Alzheimer’s Disease that occurs earlier than its more common counterpart (late-onset Alzheimer’s Disease). While the related brain changes are similar for both forms of the disorder, individuals with EOAD have a much greater variety of clinical symptoms. For example, some people with EOAD have memory problems, but others struggle with planning or making decisions, or speech and language.  Scientists still do not properly understand why such diversity of symptoms happens and what it means for patients.

Why is the study important? 

As the clinical signs and symptoms differ among individuals with EOAD, it is much more challenging for clinicians to diagnose them accurately. EOAD is also a very rare form of Alzheimer’s Disease which makes it challenging for researchers to come to conclusions about the disorder. Reviewing previously published studies helps researchers to see where the gaps in our understanding of the disorder lay. It also provides a clearer direction of what further research is necessary to understand how and why EOAD happens.

What did the authors do and how did they do it? 

The authors searched for all published articles on the topic of EOAD and grouped them into different categories. Within these categories, they summarised the key findings. The most important category was related to genes, which contain hereditary information and make us who we are. The other categories consisted of biological processes related to EOAD, different types of brain imaging studies of EOAD, and clinical features of the disorder. Grouping the findings into these categories helped the authors to comprehensively summarise what the scientific community understands so far about the related processes and brain changes.

What are the results? 

The authors found some common conclusions among reviewed articles. Then, they identified a group of genes that seems to play a role in developing EOAD. These specific genes (MAPT, PRNP, GRN) are more commonly linked with other forms of dementia, such as Frontotemporal dementia, which is characterised by changes in personality and language difficulties. The authors, therefore, think that the occurrence of these genes in EOAD might be related to why we can see such clinical diversity among people with EOAD.

The authors also summarised the findings from the brain imaging studies. That is because clinically diverse EOAD symptoms might result from the problems in the different brain structures. They concluded that structural and functional brain imaging techniques are particularly useful to characterise brain differences of each clinical variation of EOAD accurately. Structural brain imaging can then detect differences in how brain areas look. Functional brain imaging can help to detect differences in how those brain areas behave, such as by studying the pattern of blood passing through them.

What do the findings mean going forward for people with the disease?

The authors provided a summary of the key aspects of EOAD that still lack scientific understanding. This is particularly crucial going forward, as with the improvements in brain imaging techniques that are becoming more and more sensitive to small changes in the brain, scientists will be able to detect and track the development of EOAD. This review identified future research priorities for the scientists. This will help them link the missing information about EOAD with the goal to improve the diagnostic outcomes for patients.

Author

Ludmila Kucikova

Original article can be found here. 

Background 

Alzheimer’s is complex, and the precise cause of most Alzheimer’s cases is unknown. It is likely that there are several different factors which contribute to the symptoms seen. All cells in the body contain building blocks called proteins. In Alzheimer’s, certain proteins, including a protein called amyloid, form abnormal clumps in the brain. It is difficult to recreate Alzheimer’s in the lab, but one of the methods used is to treat cells with amyloid and investigate the effect this has on other parts of the cell, including the mitochondria. Mitochondria are an essential part of every cell, as they act like the cell’s batteries, providing the energy needed for the cell to survive and function efficiently. In Alzheimer’s, mitochondria do not work as well as they do in healthy people of the same age, and so this means that the cells in the brain do not have enough energy to function effectively. 

Only limited treatments are available for Alzheimer’s, and much research is focussed on finding new treatments. However, research is also looking into potential preventative strategies including diet. Previous studies have found a link between daily intake of dairy products and a lower risk of developing dementia. Other studies investigated this in mice, and it was found that dairy products which were fermented with Penicillium candidum, a fungus used in the production of some cheeses such as camembert and brie, prevented several features associated with Alzheimer’s. The specific part of the fungus which causes these effects is called beta-lactolin.

Why is the study important?

This study is important as it investigates the potential of dietary factors in the prevention of Alzheimer’s, specifically whether beta-lactolin can improve the health of the mitochondria, the cell’s batteries, and therefore improve the health of the cell.

What did the authors do and how did they do it? 

The authors first treated mouse brain cells with amyloid to recreate a cell with Alzheimer’s. They measured various indicators to show the health of the mitochondria and the cell, with and without beta-lactolin, to see whether beta-lactolin could improve any of the features seen in Alzheimer’s cells. They also did some experiments in cells taken from a person with Alzheimer’s and converted to brain cells, to see if beta-lactolin had an effect in a different model of Alzheimer’s. 

What are the results?

In the mouse brain cells treated with amyloid, mitochondria were found to function less effectively. They produced fewer energy molecules, known as ATP, and their normal and maximum work capacity was lower than in cells which were not treated with amyloid. Furthermore, the mitochondria were smaller, and the cells had a lower rate of survival. When cells were treated with beta-lactolin, many of these measures were improved; mitochondria produced more energy, normal work capacity was increased, and the mitochondria were bigger. Cells were also found to have an increased rate of survival. The authors also found that a specific protein called Mfn2, which is one of several proteins which control mitochondrial size and shape, was increased with beta-lactolin. This increase in Mfn2 might be the reason that beta-lactolin improves mitochondrial health, as size and shape are very important for the mitochondria to function efficiently. 

The authors investigated mitochondrial size further in cells taken from a person with Alzheimer’s and converted to brain cells. The mitochondria were found to be smaller in the cells from a person with Alzheimer’s compared to healthy cells. They also found more mitochondria in the centre region of the cell, which usually means there is an increase in the number of mitochondria which are not working correctly. Treatment with beta-lactolin increased the number of longer mitochondria, again suggesting that beta-lactolin has an effect on mitochondrial size. 

What do the findings mean going forward for people with the disease?

This is the first study to show that beta-lactolin can improve the health of the mitochondria in Alzheimer’s cells. The use of a food-derived treatment to improve mitochondria function is an original approach to improving cell health in the brain. While more research is needed to confirm these findings, this study may indicate the potential of beta-lactolin as a way to reduce the risk of developing Alzheimer’s. 

Author

Katy Barnes

Original article can be found here. 

Background 

Our brain contains thousands of connections that ensure optimal communication between various areas. This is very similar to how roads connect town regions and ensure communication between them. In a road analogy, some connections might be disrupted because of heavy traffic or because of an accident, which results in slower traffic on that route. In some disorders such as Alzheimer’s disease, we see a similar pattern of disrupted brain connections.

In the concept of brain connectivity, we distinguish between structural and functional connections. Any neighbouring brain regions are structurally connected. On the other hand, two or more brain regions are functionally connected when they are simultaneously active as a response to a particular stimulus, regardless of their structural connections. This results in formation of brain networks. For example, some regions are simultaneously active when we are at rest doing nothing, and this activity forms so-called resting-state networks.

By using brain imaging, previous research found that both structural connectivity and functional connectivity in patients with Alzheimer’s Disease differed from those in healthy individuals. Particularly, structural differences were observed in connections from and to brain areas related to memory and functional differences were observed in multiple resting-state networks.

Why is the study important? 

Brain imaging tools can detect brain differences associated with dementia and can be used to predict which patients with cognitive impairment might progress to developing Alzheimer’s disease. However, the use of brain imaging to diagnose Alzheimer’s is currently limited to assessment of brain shrinkage, which is unable to capture the disorder early enough for effective treatments and therapies. Therefore, exploring new methods such as Alzheimer’s-related changes in brain connectivity might results in earlier and more accurate diagnosis.

What did the authors do and how did they do it? 

The authors scanned brains of people with Alzheimer’s Disease as well as healthy individuals by using Magnetic Resonance Imaging (MRI) which is a safe medical test that uses magnets and radio waves to create a detailed picture of brains. They were specifically interested in exploring structural connections between regions that relate to memory. Their next step was estimating functional resting-state networks by using statistical tests on brain areas that displayed simultaneous activity when individuals were laying still in the scanner. The authors then compared the anatomical connections and functional resting-state networks between patients with Alzheimer’s and healthy individuals.

What are the results? 

The authors found several differences in brain structural and functional connectivity in patients with Alzheimer’s. The patients’ structural connectivity was reduced between the regions that were linked with problems in memory and attention. The regions specifically linked with memory were also shrunk. In addition to these structural changes, the authors observed reduced activity in functional resting-state networks in Alzheimer’s patients, which is in line with previously published studies.

What do the findings mean going forward for people with the disease?

The authors compared the relevance of measured brain imaging features for clinical practice and concluded that brain connectivity changes related to Alzheimer’s were reflected in many of them. These findings validated that connectivity-related changes in Alzheimer’s disease have the potential to be incorporated in standard screening practices which could improve diagnostic accuracy and result in earlier diagnosis.

Author

Ludmila Kucikova

Original article can be found here. 

Background 

Alzheimer’s disease (AD) is a devastating neurodegenerative condition in the elderly and the most common form of dementia. This neurodegenerative condition is caused by the progressive loss of structure and function of nerve cells (neurons), that may ultimately lead to neuronal death. AD is characterised by the accumulation of insoluble, sticky protein products known as amyloid beta plaques (containing the protein amyloid beta) and neurofibrillary tangles (containing the protein TAU) in the brain. AD patients suffer with a gradual decline in memory, thinking and reasoning skills. Therapeutic interventions are ongoing, targeting the removal of the accumulated insoluble protein/s, but this approach alone may not be sufficient to reverse functional deficits in the AD brain. 

Advanced therapy medicinal products (ATMPs) are medicines for humans that are based on genes (which are the coding sequence for proteins), tissues or cells. They offer revolutionary new opportunities for the treatment of disease and injury. Therefore, gene therapies that target neuroprotection (stops neurons from dying) may be an effective option to treat individuals suffering from AD. Gene therapy is a technique that modifies a person’s genes to treat or cure disease. Gene therapies involve various approaches such as replacing a disease-causing gene with a healthy copy of the gene; inactivating a disease-causing gene that is not functioning properly; or introducing a new or modified gene into the body to help treat a disease. 

Both animal studies and human studies have shown that there is less of the protein Caveolin-1 (Cav-1) in diseased neurons in AD. Cav-1 plays a critical role in neuroprotection and thus, preserves higher cognitive functions such as learning and memory in the brain. 

Why is the study important? 

In this study, Cav-1 was chosen as a gene therapy candidate. Tests were performed to see whether Cav-1 gene therapy in an experimental mouse model of AD (PSAPP1) could improve higher brain function. PSAPP mice exhibit learning and memory deficits at 9 and 11 months, respectively, which is associated with decreased expression of Cav-1. Thus, this study provides vital information about how beneficial Cav-1 gene therapy can be in an AD mouse model and suggestive of further assessment in other neurodegenerative diseases.

What did the authors do and how did they do it? 

The authors categorised PSAPP mice in two groups. One group of animals were treated with Cav-1 gene therapy. Animals in another group were not treated with anything, used as control group. The authors looked at the behaviour2 of the mice and the internal structure (morphology) of the neurons at the age of 9 months and 11 months. PSAPP mice that had been treated with Cav-1 gene therapy were compared with the control mice.

In this study, the behavioural tests named as open field and fear conditioning were used to understand the behaviour of each mouse. In the open field test, the exploratory and locomotor (movement in a transparent apparatus) activity of mice is recorded. The apparatus consists of an arena surrounded by high walls, to prevent escape, and the floor of the open field is divided into squares. The mouse is placed in the apparatus and the number of square crossings, rearing, and time spent moving are used to assess the activity of the rodent. Higher exploration and locomotion activity suggests normal behaviour of mice. 

Moreover, the fear conditioning test is used to study fear learning and memory in mice. Fear Conditioning is a type of associative learning task in which mice learn to associate a particular neutral conditional stimulus (a tone) with an aversive unconditional stimulus (a mild electrical foot shock) and show a conditional response (such as freezing). After repeated pairings of tone and electrical foot shock, mouse learns to fear both the tone and training context. 

What are the results?

PSAPP mice treated with Cav-1 gene therapy had elevated levels of the Cav-1 gene. Furthermore, the open field and conditional fear learning tests show that the mice which were not treated with Cav-1 gene delivery exhibited reduced learning and memory recall. In contrast diseased mice with elevated levels of the Cav-1 gene kept their memory recall function at the age of 11 months.

Furthermore, the morphology of the neurons was studied using microscopy. Various markers (proteins responsible for the maintenance of morphology in healthy neurons) were used to study the morphological changes in neurons. The localization and levels of markers of interest were assessed using advanced molecular biology techniques.

In summary, this study demonstrates that Cav-1 gene delivery delays neurodegeneration and cognitive deficits in PSAPP mouse model of AD.

What do the finding mean going forward for people with the disease?

Findings from this study suggest that Cav-1 might serve as a novel gene therapy target to preserve or delay neurodegenerative conditions in AD and other forms of brain disease of unknown causative factors.

Author

Amisha Parmar

Original article can be found here. 

Background 

Mitochondria act as the batteries of the cell and are vital to the health of cells. Therefore, it is detrimental to cell health if mitochondria are not working properly. Dysfunctional mitochondria must be removed from cells by a process called mitophagy. This happens continuously in healthy cells but is impaired in diseases like Alzheimer’s, causing an accumulation of damaged mitochondria. It’s thought that if compounds can be used to repair or regulate this process, they could be a potential therapy for Alzheimer’s Disease. 

Why is the study important? 

This study further supports the theory that defects in the removal of faulty mitochondria (mitophagy) play an important role in Alzheimer’s disease, and restoring this process might be an effective therapeutic approach. The authors designed a new method to use Artificial Intelligence (AI) combined with testing in various cell and animal models to identify potential compounds. 

What did the authors do and how did they do it: 

By combining various AI methods to scan through a collection of thousands of drugs from traditional Chinese medicine, the authors identified 18 compounds that had the potential to increase the removal of damaged mitochondria. Their approach with AI integrated basic chemical information with more complex data about specific areas of the compounds to predict what activity and action each may have. To narrow down the selection and determine the best compounds, they performed tests in cells, nematode worms, and mice; all with mutations to mimic Alzheimer’s. 

The process of damaged mitochondrial removal was quantified in worms and mice alongside behavioural studies to examine whether there were improvements on memory. Furthermore, they investigated whether treating mice with the two lead compounds resulted in a reduction of amyloid beta in the brain. This is one of the proteins that forms clumps in the brain which are a hallmark of Alzheimer’s disease.

Although animal models are important for drug discovery, the results do not always translate into humans. Differences in the brains and bodies of the animals in comparison to humans, and the fact that only certain aspects of the disease are mimicked in the models, mean that compounds in animals may not have the same effect or outcome in humans.

What are the results? 

After experimenting in cells and worms, two lead compounds were selected - Keam and Rhap. These compounds were amongst the hits from the initial selection identified by AI. The scientists determined that this methodology had a 44% success rate, much higher than other traditional methods. The compounds were shown to improve memory in worms and mice, as well as reducing the clumping of the harmful proteins implicated in Alzheimer’s - amyloid beta and Tau. 

What do the findings mean going forward for people with the disease? 

This study is important as the authors have developed a method utilising AI to narrow down a collection of thousands of compounds to a select few which can be tested in animal models. This methodology has identified two compounds that could be taken forward into further testing and clinical trials. 

When compared to other drug screening methods, the authors determined that the one described here had a much higher success rate. Additionally, the same method could be used for other neurodegenerative diseases. 

Although the compounds have shown promise, it’s possible that increasing the removal of damaged mitochondria could be detrimental, and there are concerns whether Rhap is able to pass from the blood into the brain where it is needed. 

Nevertheless, this study presents a new way to combine AI with traditional experimental work, accelerating the discovery of new drugs.

Author

Emily Mossman

Original article can be found here. 

Background 

Ceftriaxone is an antibiotic already used to treat bacterial infections. There is evidence from previous studies that this antibiotic also has an ability to protect the brain; Ceftriaxone can restore cognition in rats with Alzheimer’s as well as altering genes related to the protein amyloid beta. This protein plays a key role in Alzheimer’s. Amyloid beta clumps together to form ‘oligomers’, and it is this form of the protein that is most toxic. Therefore, if Ceftriaxone alters amyloid beta, it may be beneficial in treating Alzheimer’s. 

Why is the study important? 

This study provides further evidence that Ceftriaxone could be a potential treatment for early Alzheimer’s. It aimed to determine whether the drug could have a beneficial effect on the behaviour of mice with early Alzheimer’s, as well as the amount of amyloid beta and inflammation in their brains.

It is also important as it is an example of drug repurposing. This is a relatively new approach and aims to use existing drugs for one condition to treat another disease. Because the drug is already approved and is safety tested, it can progress through clinical trials much faster. 

What did the authors do and how did they do it? 

In order to mimic Alzheimer’s in mice, the authors injected amyloid beta into their brains. For comparison, they also injected the other half of the mice with water. These mice do not display the symptoms of the disease. Some mice in both groups were given Ceftriaxone, whilst the remaining animals were given a placebo. It was therefore possible to compare mice mimicking Alzheimer’s that had been given Ceftriaxone to those that had not, as well as compare them to mice that did not have the disease.  

They then used several behaviour tests to examine different aspects of the mice’s’ memory and assessed whether Ceftriaxone caused any improvement. These tests were mainly different forms of mazes where the mice had a certain goal. The authors also took samples of the mice’s brains to examine inflammation in certain areas.

What are the results? 

It was found that Ceftriaxone improved various aspects of the mice’s memory in some of the behavioural tests. In some instances, mice with Alzheimer’s given the drug performed better than those with the placebo. In one test, the drug restored the mice’s memory to a level equivalent in those without the disease. 

Whilst not seen in all areas of the brain, inflammation was lower in diseased mice that had received Ceftriaxone compared to those who had not. The regions of the brain with this decrease were the hippocampus and frontal cortex, which are both vital in memory processing. 

The authors also investigated the presence of a type of cell, called microglia, that has an important role in inflammation in the brain. It was found that these cells were more active in the mice injected with amyloid beta compared to those injected with water. Interestingly, in the prefrontal cortex, this activity was decreased in mice treated with Ceftriaxone.

What do the finding mean going forward for people with the disease?

Although it is in the early stages, this study indicates that Ceftriaxone shows promise as a treatment for Alzheimer’s disease. The drug is able to target two key factors in the progression of the disease - inflammation and amyloid beta in the brain. Further studies into Ceftriaxone would be needed, primarily to elucidate how exactly it is working in the brain to produce the improvements in memory that have been seen in this study.  

Author

Emily Mossman

Original article can be found here. 

Background 

With age our lungs function less well, and our body gets less oxygen in our blood. Growing evidence suggests that poor airways and lung health, is linked to a decline in our brain function and may increase our risk of dementia. However, it is still unclear how poor lung health and function and decline in brain function are associated.

Why is the study important? 

Long term studies allow us to see how our bodies change over time and how this may lead to a decrease in brain function and onset of dementia. Understanding the changes in our body that may lead to dementia is vital for finding opportunities to intervene before onset of the disease.

What did the authors do and how did they do it? 

Over a period of 21 years, 1377 participants with no symptoms of dementia at the start of the study, were assessed annually for their lung function by blowing into a small device to test how fast and how much air they could breathe out. 

The participants also completed a series of tests for general brain function, memory, and perception, such as remembering a list of words or completing a pattern. 351 of the participants also had an MRI scan, which allows the scientists to produce images of inside the brain from outside our bodies and measure the size of different parts of the brain. 

The authors analysed the changes in lung function over time and how this may relate to changes in brain function and brain size.

What are the results? 

The authors found that poor lung health and function was associated with a faster decline in general brain function, memory, and perception. Additionally, they found that participants with the poorest lung health had significantly smaller sized brains than participants with good lung health. This data suggests that poor lung health may be an important factor in the risk of dementia.

What do the finding mean going forward for people with the disease?

The findings implicate the importance of good lung health on the brain and suggest that treatments to maintain lung health may be an opportunity to prevent decline in brain function and risk of dementia in later life. 

The authors suggest testing lifestyle changes, such as more exercise or stopping smoking, in older adults to see if improving lung health can improve brain function or delay the onset of dementia.

Author

Natalie Pye 

Reviewed by 

Dr Ryan West

Original article can be found here.

All cells in the body contain building blocks called proteins. In many neurodegenerative diseases, certain proteins are known to form abnormal clumps in the brain. One such protein in Alzheimer’s disease is called amyloid beta. Amyloid beta is a small, sticky fragment of protein. These small fragments stick together, and can form small clusters called oligomers, or large clumps called plaques. Previous work has shown that amyloid beta oligomers can be detected in the blood before clinical symptoms of Alzheimer’s are present.

One of the early issues often noted in Alzheimer’s is changes to vision including alterations in colour vision, sensitivity, nerve damage, and loss of cells in the eye. Amyloid beta deposits have previously been seen in the retina, both in people with Alzheimer’s and various animal models.

This study used small molecules known as ‘nanobodies’ to detect amyloid beta oligomers and plaques in the eye and brain of a mouse model of Alzheimer’s, to investigate where amyloid beta appears first, and when this occurs in relation to behavioural and memory symptoms in the mice. These mice have been given certain genes, blueprints which determine all our traits, which are associated with Alzheimer’s. This causes the mice to mimic certain biological and behavioural aspects of Alzheimer’s. Behavioural symptoms are usually seen at around 7 months, though this was not specifically tested in this study.

When the mice were 3 months of age, amyloid beta oligomers were seen in the eye, but not the brain. This suggests that the presence of amyloid beta in the eye precedes accumulation in the brain. No plaques were seen in either the brain or the eye at this age. By 8 months of age, oligomers were detectable in the brain as well as the eye, and plaques had begun to form in both. At 18 months, oligomers were no longer detectable in either the eye or the brain, but plaques had become more widespread. Neither oligomers nor plaques were seen at any age in non-Alzheimer’s mice. This data shows that amyloid beta oligomers appear in the eye months before they appear in the brain, and that plaques increase over the course of Alzheimer’s, whilst oligomers decrease.

The study then went on to investigate the presence of amyloid beta in the blood, and whether this occurred at the same time as detection of amyloid beta in the eye. Amyloid beta oligomers were seen in the blood of 3-month-old mice, suggesting that they appear in the blood either before or at the same time as in the eye.

The study also examined the localisation of oligomers and plaques within the brain and the eye, and found they occurred together. This adds support to the theory that oligomers are converted into plaques as Alzheimer’s progresses, though further research is needed to confirm this.

Finding simple ways to diagnose Alzheimer’s earlier is a key area of research. This study found that in a mouse model of Alzheimer’s, amyloid beta oligomers are present in the blood and the eye before oligomers or plaques are detected in the brain. This also occurred before memory and behavioural changes are usually seen in these mice. This raises the question of whether testing for amyloid beta oligomers in the eye and/or blood could be a potential diagnostic tool in clinical practice, which could lead to earlier therapeutic intervention, increasing the chances of slowing the progression of Alzheimer’s. However, further research is needed to confirm these findings, as well as identify if similar processes occur in human Alzheimer’s.

Author: Katy Barnes

Background

Alzheimer’s disease affects people differently, with symptoms and speed of disease progression differing between people living with the condition. Some changes in the brain related to Alzheimer’s occur years before any symptoms show. As more parts of the brain become damaged, symptoms such as memory loss and difficulties with language present, commonly known as dementia. 

Why is the study important?

To determine if a person has Alzheimer’s and estimate the time of dementia onset more accurately, biological markers (biomarkers) to track early disease-causing changes in the brain are needed. This could provide scientists with the improved ability to predict decline in brain function and indicate potential therapeutic targets, to halt the disease before it progresses to dementia.

What did the authors do and how did they do it?

Over 3 years the authors measured changes in the levels of 5 candidate biomarkers in the cerebrospinal fluid (a fluid found around the brain & spinal cord) of 111 participants with symptoms of decline in brain function but no diagnosis of dementia and 76 participants without any symptoms.

They analysed how the changes in levels of these candidate biomarkers over time might relate to Alzheimer’s development by comparing the rate of biomarker level change in participants with symptoms and participants without symptoms.

The relationship between candidate biomarker changes and brain function was also tested, using a series of questions and tests for memory, language, and logic, such as repeating a phrase back to the examiner or following a verbal command.

What are the results?

Interestingly, out of the 5 candidate biomarkers tested, the levels of 1 potential biomarker NPTX2, showed the most significant changes over the 3 years. NPTX2 is a protein in the brain important for allowing neurones to send signals and communicate.

The level of NPTX2 decreased more over time in the symptomatic participants than participants without symptoms. There was a larger decrease in participants who were positive for a known Alzheimer’s biomarker and participants whose diagnosis worsened during the experiment – essentially participants whose disease has progressed further.

Decline in NPTX2 levels correlated with decline in brain function, especially in symptomatic and Alzheimer biomarker positive participants. This correlation was also seen in participants without symptoms, suggesting NPTX2 may be a predictor of brain dysfunction prior to Alzheimer’s onset.

What do the finding mean going forward for people with the disease?

Development of a test to easily detect changes in NPTX2 would allow for earlier and more accurate predication of Alzheimer’s onset and progression to dementia. NPTX2 could also be explored as a therapeutic target, although this needs more work to be conclusive.

Author: Natalie Pye

Reviewer: Dr Ryan West

Original article can be found here.

Background: 

Some of the most important tools used in the diagnosis of Alzheimer’s are various brain imaging techniques, including magnetic resonance imaging (MRI) and positron emission tomography (PET). These can be used to show abnormalities in the brain, including the shrinking of certain areas, which is a key feature of Alzheimer’s. It is thought that the severity of Alzheimer’s symptoms correlates with the degree of abnormalities seen in the brain. However, some people with Alzheimer’s show only mild symptoms even though they have many abnormalities in their brain scans. This discrepancy may be due to several factors, but one could be the level of ‘cognitive reserve’ – this is the brain’s ability to adapt to changes, and look for alternative ways to carry out its usual functions. In other words, the brain’s resilience and capacity to deal with damage. Cognitive reserve is linked to several lifestyle factors including education, occupation, and leisure activity.

Why is the study important?

This study aims to better understand why some people show less severe Alzheimer’s symptoms despite having high level of abnormalities in brain imaging scans, and whether this is linked to various lifestyle factors. This may provide evidence for the effectiveness of various lifestyle interventions in slowing down the progression of Alzheimer’s.

What did the authors do and how did they do it? 

135 people with Alzheimer’s were recruited from memory clinics at Tokyo General Hospital and Tokyo Medical University Hospital. The authors measured the severity of Alzheimer’s symptoms using the mini mental state examination (MMSE), a commonly used test for Alzheimer’s symptoms. They also obtained two types of brain scan, and calculated the difference between these and the expected brain scan based on MMSE results. They sorted the participants into three categories; positive difference (high number of abnormalities in the brain scans, but lower levels of symptoms), no difference (similar levels of brain scan abnormalities and symptoms) and negative difference (lower levels of brain scan abnormalities and higher levels of symptoms).

They also obtained information about lifestyle including number of years in education, and longest held occupation. They assessed the type and amount of leisure activity over the last 12 months including physical activities such as walking, swimming, and sports, cognitive activities such as reading, writing, and playing games such as cards, and social activities such as volunteering, going to the cinema or a concert, and visiting museums.

What are the results?

The researchers found that age, gender, and time since diagnosis did not differ between the positive difference, no difference, and negative difference groups. However, education, and level of leisure activity was significantly higher in the positive difference group than in the other groups. The no difference and negative difference groups were similar in education and level of leisure activity. This suggests that a higher cognitive reserve (as measured by education, and levels of leisure activity) can be used to explain differences between severity of Alzheimer’s symptoms and abnormalities seen in brain imaging scans.

What do the findings mean going forward for people with the disease?

The findings of this study suggest that people with a high cognitive reserve are more likely to show milder symptoms of Alzheimer’s even when brain scans show more severe abnormalities. Whilst the precise mechanisms leading to increased cognitive reserve are not well understood, it is thought that a wide variety of leisure activities contribute, suggesting that lifestyle interventions including physical, cognitive, and social activities, may help to slow the progression of Alzheimer’s symptoms.

Author: Katy Barnes

The original article can be found here.

The World Health Organization (WHO) has made it increasingly clear that the life expectancy of an individual is rising. We can expect to live longer and more physically and socially enriched lives, though with the burden of increased risk of illness and disease. In 2018, almost 50 million people were affected by dementia, a term used to describe an individual’s rapid decline of memory, language, problem-solving and thinking abilities. In everyday life, dementia may commonly be referred to as Alzheimer’s Disease, a form of this brain disorder. The most significant risk factor for developing dementia is older age, yet there are multiple ways that the overall risk can be reduced through lifestyle changes. For decades, science and medicine have understood this using evidence from large scale studies, that have looked at the different behaviours of the population and how they influence the body. It is found that several lifestyle choices may be able to protect someone from dementia. A discussion of these preventative strategies is the main focus of the current paper, that has accumulated a vast amount of research to review how 2021 should approach dementia. 

Maintaining a healthy body is necessary to protect the brain from damage, which may help prevent or delay dementia in an individual. Studies of the population show that unhealthy lifestyle choices that include lack of exercise, poor diet, smoking and alcohol abuse, not only put someone at risk of heart disease and stroke, but also at risk of dementia. Collectively, these factors can lead to an impairment in the way that blood flows to the brain and so how the brain is able to function. 

Additionally, it is important to understand that stimulating the brain and the way the mind works may also slow the development of dementia. This may include a life that is rich in learning (education and engagement in challenging tasks) and social interaction, that may protect the brain from dementia by enhancing its ability to make two new connections and reduce the way it ages. Therefore, by encouraging a healthier and more invigorating way of living, it is possible that the rate or extent that dementia affects the population may be reduced. 

The evidence for these strategies to prevent dementia have their foundations in biology, that show that these factors are closely connected to the damage that they cause to the brain and how they contribute to dementia. Degeneration of the brain (decline and damage to brain cells), that is accelerated by cardiovascular diseases (for example, heart disease and stroke), lead to an increased build-up of dangerous cells and plaques that may advance the development of dementia. In particular, these plaques are responsible for causing a type of toxic “clumping”, that prevent brain cells from working properly. Even more, it has been consistently shown that whilst the brain has the ability of resilience (to adapt to stress and damage), and maintenance (to preserve and promote its functions), this varies between individuals and so in how much risk they are of dementia. These biological processes that leave the brain vulnerable to dementia, also extend to damaged blood vessels, of inflammation and oxygen deprivation. Choosing to engage in unhealthy habits has continued to show an increased chance of dementia through these forms of biological consequences. 

Taken together, the findings from multiple population and biology-based studies show the increased risk of dementia that lifestyle choices impose. In order to reduce the risk of dementia, it is essential that interventional programs target these dangerous behaviours that may make an individual vulnerable to the complex health risk of dementia. 

Author: Stefan Roman  

Reviewer: Jodie Keyworth

Original article here.

Alzheimer’s disease is the most common cause of dementia. It is complex, and despite much research, the precise cause remains unknown. All cells in the body contain building blocks called proteins. In Alzheimer’s disease, certain proteins, such as amyloid and tau, form abnormal clumps in the brain. Another commonly seen process associated with Alzheimer’s disease is dysfunction in a part of brain cells called the mitochondria. The mitochondria act like the batteries of the cell – providing energy for the cell to efficiently function and survive. It is thought that these two processes are linked, working together to cause brain cell death and ultimately lead to the symptoms seen in Alzheimer’s disease. 

Mitochondria are very important for the survival of the cell and so are highly regulated. Damaged and dysfunctional mitochondria are removed from the cell and recycled, in a process called mitophagy. Previously, it has been found that the presence of amyloid clumps can increase the recycling of the mitochondria. Furthermore, another protein called Miro1 has also been linked to the recycling of mitochondria, as well as the movement of the mitochondria through the cell. This study attempted to discover whether Miro1 plays a key role in mitochondrial recycling caused by the amyloid clumps. 

The researchers grew brain cells from mice and treated them with amyloid. They found that in cells treated with amyloid, the mitochondria were less efficient at producing energy than in cells that were untreated. They also found less mitochondria in amyloid treated cells, as well as increased levels of proteins associated with mitochondrial recycling. This suggests that amyloid treatment makes mitochondria less functional and leads to an increase in mitochondrial recycling. The researchers also investigated whether Miro1 was affected by amyloid treatment and found that levels of the protein decreased with amyloid treatment. 

Amyloid is known to increase the presence of highly reactive molecules in the brain called reactive oxygen species (ROS). These molecules are a natural by-product of energy production and are usually removed by proteins called antioxidants, but when their levels are increased by amyloid, the antioxidants are not able to remove them as efficiently. When a ROS scavenger, a molecule which mops up excess ROS, was given to the cells, many of the changes seen with amyloid treatment including reduced Miro1 levels, were reversed. This suggests that the effects of amyloid on the mitochondria were caused by an increase in ROS. 

To determine whether the decrease in Miro1 played a key role in the other changes seen, the researchers replaced the Miro1 that had been lost in the amyloid treated cells. This was seen to reverse many of the changes that were caused by amyloid treatment. 

To investigate these processes in a more complex model of Alzheimer’s disease, the researchers studied mice whose genes, which are like a blueprint for all living things, had been altered to give them Alzheimer’s like symptoms. They saw similar results in the Alzheimer’s mice as they did in the cells treated with amyloid. 

The researchers concluded that amyloid increases ROS levels, which in turn increase mitochondrial recycling via a reduction in Miro1. These results improve our understanding of the relationship between Alzheimer’s disease, amyloid, and mitochondria and may help in the development of a novel therapeutic target for Alzheimer’s disease. However, further study is required to better determine the importance of Miro1 in Alzheimer’s disease. 

Author: Katy Barnes

Original article here. 

Frontotemporal Dementia (FTD) is the second most common form of early-onset dementia, but no effective treatments are currently available. Although FTD symptoms are highly variable, the presence of harmful deposits of proteins in the brains of patients results in distinct disease subgroups. The toxic protein deposits consist of either TDP-43 or tau, which cause FTD through different mechanisms and will likely need different treatments. This poses a major problem for researchers, as at present we are only able to confirm whether a patient has the TDP-43 FTD or the tau FTD when the brain is examined after death. FTD research is slow partly because in life we cannot tell if someone has TDP-43 FTD or tau FTD. This means we are unable to decide whether a patient should go into trials of drugs to treat TDP-43 FTD or tau FTD. Before we can test treatments in patients with FTD we must be able to determine which type of FTD they have. 

About 50% of FTD patients have TDP-43 pathology, but so far efforts to detect TDP-43 itself in living patients have been unsuccessful. A team of researchers have attempted to overcome this issue, by looking for changes or ‘biomarkers’ in the bodies of people with FTD, that mark them out as having TDP-43 FTD. In this paper they explore the relationship of stathmin-2 with TDP-43 and its suitability as a biomarker. Stathmin2 is a protein found in nerve cells that has functions linked with repair and maintenance of the nerve cell structure. 

First, the researchers used nerve cells grown in a lab, showing that a shortened version of the protein known as truncated stathmin-2 accumulates only in the presence of the harmful TDP-43 deposits. Next, they used post-mortem brain tissue donated from FTD patients, and extracted RNA – the set of instructions cells use to make proteins. The shortened stathmin-2 RNA was found to be higher in the TDP-43 FTD patient group, but importantly not in individuals without any neurological disease, or those with PSP, a different neurological disease associated with tau but not TDP-43. This indicates shortened stathmin-2 may be specifically associated with TDP-43 pathology, and therefore may be viable as a biomarker. Researchers believe this is because TDP-43 directly regulates stathmin-2. They argue that in FTD, TDP-43 becomes dysfunctional, and only then does this lead to the production of the shortened form of stathmin-2. Therefore, if researchers can detect the stathmin-2 in this shortened form it shows the patient must belong to the TDP-43 group. 

This study is not exhaustive, and the authors raise several significant challenges ahead before stathmin-2 could be used in a clinical setting. More work is needed to establish that shortened stathmin-2 is a true proxy for TDP-43 pathology and will be sensitive enough to reliably detect TDP-43 patients without misidentifying patients with other pathologies. The study authors highlight the need to determine the point in FTD in which shortened stathmin-2 begins to accumulate, as the best biomarkers should detect the earliest stages of disease where the likelihood of successful treatment intervention is highest. However, the major question unanswered by this study are the practical issues around shortened stathmin-2 detectability. Its usefulness as a biomarker hinges largely on the ease of detection in patient blood or spinal fluid. While these important questions require much more work to answer, this remains an interesting study that reflects the research community’s increased focus on biomarkers as essential for FTD research progress. 

Author: Bridget Benson

Original article here.