XZ: Interesting. I have little knowledge about sleep, but I can understand that sleep has different effects at different levels in humans and animals, such as memory, behaviour, and sports. Sleep is important to us, I think we should try to sleep well.
Marieke: Yes, I am hoping that in the future, our acknowledgement of the importance of a good night’s sleep will be similar to other lifestyle changes, such as exercising, diet and smoking. Thirty years ago, people were smoking and now many people have quit or did not start, because as a society we have embraced that it is unhealthy. Maybe it will be the same with sleep at some point. There are so many associations between too little or bad quality sleep, and disease prevalence and severity, and one of those is dementia.
XZ: Of course. I imagine we do not yet clearly understand the mechanism of the relationship between sleep and dementia, but could you please just introduce, according to your knowledge, what we know about the two and how they might be linked?
MH: We are still in the dark regarding mechanisms, but I can tell you a couple of things. First, an observation. If people are already suffering from dementia, we see that they are sleepier during the day and are more awake during the night. Another circadian hallmark of dementia is a behaviour called sundowning. What happens in a subgroup of dementia patients is that they become very restless when the sun is about to set, they become agitated and sometimes even aggressive. These symptoms are very difficult for the caretakers, and one of the main reasons that dementia patients are institutionalised. The sleep and circadian aspects of dementia are too heavy a burden on the carers.
Studies suggest that in the pre-clinical stage of dementia, before people are showing cognitive symptoms, and around the same time when, amyloid-beta (Aβ) (a protein fragment and biological hallmark of dementia) levels are rising, there are also reports of disturbed circadian rhythms. For example, it was reported that people who later developed dementia had before that, already a reduction in amplitude of their circadian rhythm. This can mean two things: either the changes in circadian rhythms are following the disease progression very closely, or they are actually contributing to it. This is an open question that we need to investigate.
Aβ and tau aggregates are markers for Alzheimer’s disease progression. However, what is interesting is that both proteins fluctuate in phase with waking, and upon extended wakening, their levels in cerebrospinal fluid increase, both in mice and humans. This is a very acute effect. So, how does that link to toxic amyloid beta or tau aggregations? Animal studies in Alzheimer's disease mouse models have shown that multiple sleep deprivations can lead to accumulation of Aβ, and this is a potential mechanism by which sleep fragmentation leads to AB aggregates. Moreover, a couple of years ago, the so-called ‘glymphatic system’ was proposed. It is a sort of waste drainage for our brain, and this system seems to be more active during sleep, thereby allowing for drainage of Aβ from the brain. With all these observations in mind, we have increased levels of Aβ and tau during waking, and a decrease during sleep. However, one of the struggles that we have with this hypothesis is that some patients don’t have typical Aβ aggregates in their brains. I think the idea that disturbed sleep patterns generate toxic protein aggregates is a good starting point, but it is does not fully explain the relationship between sleep loss or sleep disturbances and Alzheimer's disease.
Another possible mechanism could be through inflammation, which is a line of research we’re also investigating in Marco’s lab. Inflammation in the brain contributes to Alzheimer's disease progression, and circadian rhythms regulate inflammation as well. My research focuses on a specific group of temperature sensitive proteins that are neuro-protective. I want to understand if these proteins change with sleep-wake state, and, assuming that sleep is disturbed in people with Alzheimer's disease, if a sleep-dependent change in these proteins contributes to the development of the condition.
XZ: OK, I see now there are a lot of potential hypotheses. Do you think sleep can improve or treat dementia, not at a molecular or cellular level but at a behavioural level? For example, could people living with dementia modify their sleep habits to improve their health?
MH: I must put this disclaimer: I am more a mouse sleep researcher; Derk-Jan Dijk is a human sleep researcher in the UK DRI Care Research & Technology Centre and he might be one of the best people to put this question to. However, there is a simple intervention that I can mention, which is light.
Light conditions affect how people are sleeping in general. In care homes, lights are often on, which makes it easier for people to work during the night. However, for the patients, it makes it more difficult to have a good sleep-wake pattern. It's not only during the nights that you want to dim the lights, but also during the day you want to increase the brightness of the light, which is going to help people to be more alert during the day. There are a couple of studies that have shown that changing the light conditions improves the wellbeing of people.
XZ: You answer my questions very well. What are the challenges in exploring or investigating how sleep can improve the health of people with dementia and healthy people? Do you see any potential solutions to solve these challenges?
MH: I think one of the challenges that we have in sleep research is that we can keep people or animals awake but we cannot force them to sleep. You can mimic a sleep-like state with drugs, but it won’t be exactly the same as natural sleep. Also, if you force people or animals to be awake in an experimental situation, this is not necessarily mimicking their sleep-restriction situation.
One of the other challenges that we face in sleep research is that we are focusing a lot on the brain and neuronal activity as a determinant of whether somebody is awake or asleep. The gold standard measures in sleep research are electroencephalography (EEG) and electromyography (EMG) based sleep-wake-determination. We narrow ourselves only to brain or neuronal activities, whereas sleep is much more than that. I think, to be able to determine more accurately what sleep is, we need to keep an open mind and not only look at EEG and EMG. Maybe if we do that, we can find some other traits that are also changing with the sleep-wake state, and these may be predictive in terms of disease development.
I also wanted to add that, in sleep research, a lot of attention has been focused on NREM sleep, also known as slow wave sleep, maybe just from using a historical perspective. But there’s another sleep stage called rapid eye movement (REM) sleep, which we spend less time in. There's more and more evidence now suggesting that this is also a very important part of our sleep and helps us to feel refreshed and perform better. So, we need to keep an open mind, to look out for different ways of studying sleep, and reconsider what aspects of sleep we study.
XZ: Okay, good. We have discussed the phenomena, mechanisms, and challenges in sleep research. Could you please also introduce several recent and novel technological advances in your research area that have aided research? For example, like EEG was- now a very classic but important technology.
MH: I think, in neuroscience, we have all benefited a lot from optogenetics- the ability to control neural activity using light. We can now manipulate the activity of neurons and astrocytes and that really gives us the ability to answer more causal questions. It's not specific for sleep but it's important. There's also the use of viruses to manipulate gene expression. Marco showed using AAVs (Adeno-associated-viruses) that it’s not only neurons, but also astrocytes that are important in the biological clock. So, these are important tools that interfere with biology, allowing us to investigate specific mechanisms.
I think the fact that we are collecting more and more diverse data from human subjects around the clock is another important advance. I remember from one of the talks from the UK DRI Care Research & Technology Centre that they are measuring where people are at certain times of the day, and what kinds of activities they do in a home-like setting. From the scientific perspective this is exciting because it can reveal something that we would not see in a laboratory situation, where people behave differently.
There are also a lot of new devices that have come on the market that can measure physiological parameters that correlate with sleep. Although they are not measuring EEG and thus are not the gold-standard in sleep research, there might be a lot of valuable information in them because there are so many people using them.
XZ: Thank you very much for introducing so many different techniques in your research area. I know of optogenetics and EEG, but I am not familiar with virus-based manipulation. I can only generally understand how to use viruses to insert some genes into a specific neuron, but this is a wonderful technique. I know have some general questions. As a researcher, what drives your passion for your research?
MH: I'm still very interested in the link between your brain and how that determines who you are as a person and pursuing that question from a sleep perspective has been a huge motivator. What I really like in research is that one day is not the same as the next. For example, one day you need to solve an analysis problem, the next day you need to design your experiment, then you need to learn how to use this new device, and then you are supervising a student. There are so many different aspects of this life and I'm super grateful that I have the opportunity to learn so many things.
XZ: I get a similar feeling when I learn something new. It’s cool, but sometimes in daily research, I meet some challenges. For example, if I need to set up some devices or software or solve some technical problems. It’s somewhat frustrating but also interesting. We should embrace both the positive and negative sides in research. Ok, now, this is my last question. Has the COVID-19 pandemic introduced some challenges to your research, because I know your research is lab experiment based? If yes, how did you address these challenges?
Marieke: Like many other labs, during lockdown, we had to stop most of our experiments. What I really liked is that we had virtual coffee every day via video chat during the lockdown with the whole lab. So, we kind of kept checks on each other, which is important because it can be quite lonely in this lockdown situation, especially if you're from overseas. From a scientific point of view, it gave us the opportunity to catch up on things that are important to do but easily left behind in the day to day lab business, and to reflect more on the bigger picture. It’s great to be back in the lab now though, everybody is helping each other out to get as much done as possible.
XZ: I can empathise with your feelings during this time. In lockdown, I also had time to think about the bigger picture with regards to my research. That’s all the interview questions I have. Thank you very much. I enjoyed this interview and have learnt a lot form you.
MH: Thank you for this interview Xiaoqi.
