A decades-long search for a dementia-causing toxin

Interest in the correlations between environmental toxins and neurodegeneration focused the world’s magnifying glass on the island of Guam in the 1950s due to an unexpected increase in cases of neurodegenerative cases among the indigenous CHamoru population. The specific condition that temporarily affected Guam is known as amyotrophic lateral sclerosis-parkinsonism dementia (ALS-PDC) and known locally by the CHamoru term lytico-bodig.

A focus on this isolated cluster of cases led to decades of pursuit of causal toxins found in seeds of Guam’s native cycad tree. These seeds were components of the local cuisine at the time, and increased reliance on this form of food starch during World War II was a plausible hypothesis to explain the increase in neurodegeneration cases shortly after the war.

Several factors likely coalesce

An ebb and flow of sequential disappointments has evolved since the 1950s because the identification of a single causal cycad toxin remains elusive.

But these disappointments have been countered by successes. It is now understood that several factors likely coalesce into a synchronized perfect storm to generate an unusual increase in localized neurodegenerative cases, such as what temporarily happened on Guam. These co-factors may include exposure to high doses of the environmental toxin by the most susceptible gender with the most susceptible genes at the most susceptible age, followed by a latency period before the neuronal damage begins to express itself.

The UOG-UBC collaboration has lasted more than two decades, and various members of the team have authored more than 100 journal articles on various aspects of cycad biology during that time. The toxicology of Guam cycad seeds was the subject of 14 of these publications.

“When I began collaborating with UOG, we had the benefit of building on the foundation of decades of research from Guam,” said co-author Christopher Shaw, UBC neuroscientist. “We used the fact that no plant scientist had been directly involved in any of the previously published research to secure funds to revisit various issues concerning cycad seed toxins.”

Difference between acute and slow-acting toxins

One of the many confusing aspects of this research is that acute toxins, which cause immediate poison reactions following cycad seed ingestion, are distinct from slow-acting toxins, which lead to neurodegeneration.

“The distinctions between these two forms of toxins are often confused, and scientists are constantly reminding the public that many years need to elapse after the exposure to a slow plant toxin before negative health outcomes develop,” said Benjamin Deloso, a cycad biologist with UOG.

Claims of cyanide poisoning inaccurate

Another benefit from the marathon pursuit of the causal cycad toxin is that an enormous body of literature has developed that uncovered which biomolecules are not at play. “This is how science works,” Shaw said. “The aggressive empirical look at each candidate toxin was justified and refined the development of superseding hypotheses that were vigorously tested.”

For example, cassava roots contain sugar-based molecules that liberate cyanide after ingestion by mammals, and cycad seeds contain similar molecules, but cycad seeds contain no free cyanide and the identified sugar-based cycad molecules in cycads are incapable of liberating toxic levels of cyanide following ingestion by mammals. The meticulous research revealed the claims of cyanide as a potential cycad toxin and that cycad seed consumption could cause cyanide poisoning were inaccurate.

“Throwing around fear-mongering buzzwords, like cyanide, is a classic example of a repetition of false information in order to drive a personal agenda,” Deloso said. “There are even petitions being circulated that falsely claim that cycad plants contain cyanide in attempts to force retail nurseries to stop selling cycad plants to pet owners.”

The research team contends that scientists are not immune from the mistake of repeating these sorts of false claims about cycads. This tends to happen when scientists get their information from the gray literature or online encyclopedia style websites that are not vetted by cycad experts.

The authors hope that one outcome of their new publication is a decline in the spread of false information about cycad poisoning, as these untruthful statements damage the international community’s attempts to improve cycad conservation.

In a study published this month in Scientific Reports, researchers from The University of Tokyo Institute of Industrial Science have shown that a recently developed flood forecasting system provides much earlier advance warnings of extreme flooding events than current systems. Floods are one of the most common natural disasters and are increasing in frequency. In 2019, Typhoon Hagibis swept across parts of Japan causing severe flooding that resulted in 86 deaths and approximately 400 billion dollars’ worth of damage. Most urban areas in Japan lie within a floodplain and typhoons can result in rapid and dangerous flooding. Early warning systems can help people to prepare for imminent flooding, but people need sufficient time to do so.

“Current warning systems can provide accurate flooding predictions, but with only a few hours’ notice” says lead author of the study Wenchao Ma. “Because people need more time to respond effectively to flood warnings, we investigated whether a newly developed flood forecasting system could accurately predict flooding locations with a longer lead time.”

Flooding predictions in Japan are currently based on gauged upstream water levels. The new system is based on models of the land surface and river routes that used together can simulate the movement of water in floodplains. These models are combined with meteorological data like rainfall, temperature, and wind speed, and statistical analysis; the result is flood predictions for all rivers in Japan.

One of the main challenges with forecasting floods is a lack of data to validate the techniques used. During a disaster, collecting information about floods is challenging and can be dangerous. To overcome this issue, the team looked at the location and timing of dike breaks during Typhoon Hagibis. Dike breaks are a good indicator of which areas flooded during the typhoon and allowed the researchers to test the ability of the forecasting system to predict flood locations.

“The system was very effective,” explains Kei Yoshimura, senior author. “In fact, we found that the model accurately predicted flooding at 91% of broken dike locations.” Importantly, the system also predicted floods with a 32-hour lead time — a notable improvement on the current system. This extra time could be helpful for disaster preparation and making decisions about evacuation.

As the frequency of flooding is likely to increase in the future, forecasting systems that produce accurate and timely flood warnings are urgently needed in Japan, and the rest of the world.

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Materials provided by Institute of Industrial Science, The University of Tokyo. Note: Content may be edited for style and length.

These results were published in the academic journal NeuroImage on May 23, 2021.

Main Points

• The researchers showed that people who are physically active during childhood (up to 12 years of age) have higher cognitive functions in later life.
• However, they could not find a correlation between cognitive function and post-childhood physical activity.
• The positive association between childhood exercise and cognitive function was evident in the modular (*1) segregation of brain networks, strengthened inter-hemispheric connectivity, greater cortical thickness, lower levels of dendritic arborization and decreased density.
• During childhood, the formation of the brain’s network is susceptible to environmental and experience-related factors. It is thought that exercise during this period optimizes brain network development and is linked to the maintenance and promotion of cognitive function in later life.

Research Background

Research over the previous decade has shown that exercise during childhood affects the development of cognitive functions. Recent findings have indicated that these benefits of childhood exercise extend to the maintenance and promotion of cognitive functions in middle age and later life. However, the changes in brain functionality and structure related to this positive association have yet to be illuminated. This research study investigated the relationship between physical activity in childhood and cognitive function in later life, using MRI (magnetic resonance imaging) to illuminate the structural and functional changes in the brain that are behind this relationship.

Experiment Method

The research group conducted a study on 214 participants ranging in age from 26 to 69 in order to investigate the relationship between childhood exercise and cognitive function, and the underlying functional and structural neural networks and cortical structure. Childhood exercise was assessed via questionnaire. One aspect of cognitive function, response inhibition (the ability to suppress inappropriate behaviors), was measured using a Go/No-go task. The image data from the MRI was analyzed and the following were calculated: structural and functional connectivity (*2), cortical thickness, myelination, the degree of neurite orientation dispersion and density index. The brain was divided into 360 areas in accordance with the Human Connectome Project (*3), and functional and structural parameters were obtained for each area. In the statistical analysis, information obtained through the questionnaire was used as confounders. This included each participant’s educational background, parents’ educational background, number of siblings and exercise during adulthood.

Experiment Results

Firstly, the researchers analyzed the relationship between whether participants exercised during childhood and Go/No-go task performance (false alarm rate). They found that participants who exercised during childhood (up until age 12) had a lower false alarm rate than those who didn’t (Figure 1). Furthermore, this correlation was found regardless of the age of the participant. However, no such relationship was found between task performance and post-childhood exercise.

Next, the research group investigated structural and functional connectivity in the brain relating to Go/No-go task performance in participants who exercised during childhood. From these results, they confirmed that in terms of structural connectivity in the brain, there were positive associations (Figure 2A: connections indicated in red) and negative associations (Figure 2A: connections indicated in blue) between exercise during childhood and the false alarm rate in the Go/No-go task. Large-scale network connectivity was found in over half (73%) of structurally connected areas that were positively associated with the Go/No-go task false alarm rate (Figure 2B, left portion). On the other hand, inter-hemispheric connectivity was found in the majority (88%) of structurally connected areas that were negatively associated with the task’s false alarm rate (Figure 2B, right portion). In terms of connections between functional areas, connections showing positive associations (Figure 3A: connections indicated in red) with the Go/No-go task false alarm rate were identified in participants who exercised during childhood but no negatively associated connections were found. Furthermore, large-scale network connectivity was found in the majority (91%) of connected areas that were positively associated with the task’s false alarm rate (Figure 3B, left portion).

In those participants who did not exercise during childhood, there was no structural or functional connectivity identified in relation to the false alarm rate in the Go/No-go task. Lastly, the researchers investigated cortical structure parameters in relation to the Go/No-go false alarm rate for participants who exercised as children. They found that task performance was negatively associated with cortical density, and positively associated with the degree of neurite orientation dispersion and density.

The above results demonstrate that modular segregation and strengthened inter-hemispheric connections in the brain networks of people who exercised during childhood reduced the number of mistakes that they made in the Go/No-go task.

Glossary

1. Module: A single unit that combines with others to form the entire structure of a system. The human brain has a clear modular structure: it is divided into a number of large-scale networks made up of multiple areas.

2. Structural and Functional Connectivity: This refers to the structural and functional relationships between different areas of the brain. Structural connections between areas of the brain can be identified by anatomical nerve fiber connections, and functional connections are indicated by similarities in patterns of neural activity.

3. Human Connectome Project: This large scale research project began in North America in 2012 and aims to deepen understanding of brain connectivity.

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Materials provided by Kobe University. Note: Content may be edited for style and length.