Audrey Low has just completed her PhD on the role of cerebral small vessel disease in dementia
Research group: Old Age Psychiatry
Supervisor: John T O’Brien and Hugh Markus
Can you give us a short background into what your PhD was about?
As my thesis title suggests, my PhD research investigated the role of cerebral small vessel disease (SVD) in dementia. The brain’s small vessels are more susceptible to injury than larger vessels, and when they are damaged, that’s how SVD occurs. The brain has very high energy demands and a limited capacity for energy storage. Therefore, it relies heavily on the vessels to provide a continuous oxygen supply. When the blood vessels are damaged, the blood supply is impaired, which can result in cell death and other adverse effects. SVD is increasingly recognised as a key player in dementia, cognitive impairment, and stroke. But its role in the pathogenesis of Alzheimer’s disease is still not well understood.
So, the aim of my PhD project was to further our understanding of SVD in dementia using a two-pronged approach – by examining how SVD relates and interacts with (1) hallmark pathologies of Alzheimer’s disease and (2) well-established dementia risk factors at midlife, before the onset of symptoms.
How would you sum up your main findings?
My research culminated in six studies, split into two sections. The first half of my thesis demonstrated that the main neuroimaging signs of SVD were related to PET markers of neuroinflammation and tau, and plasma amyloid-beta. Interestingly, associations with amyloid and tau markers were largely observed in relation to white matter lesions, which represent microstructural injury to the white matter of the brain and can also be attributed to other neurodegenerative mechanisms.
The second half of my thesis was conducted within the PREVENT-Dementia study (https://preventdementia.co.uk/). The majority of dementia research is conducted in elderly or symptomatic individuals who already show signs of vascular and Alzheimer’s pathology, which makes it difficult to separate and distinguish the effects of each. That issue was mitigated by the composition of our PREVENT-Dementia cohort, which is made up of cognitively healthy middle-aged participants. And what we found in this study was that inherited predisposition to dementia (APOE4, parental family history of dementia) was related to longitudinal progression of SVD over time, but not baseline SVD severity at a single time-point. On the other hand, modifiable risk factors of future late-life dementia (e.g., hypertension, physical activity, BMI) were associated with SVD burden well before expected dementia onset, as early as midlife. These results position SVD as a key factor in early dementia pathogenesis and suggest that SVD may account for a sizeable proportion of dementia risk conferred by these well-known risk factors, which may be preventable.
And across all the studies conducted, there was an interesting regional pattern. Our comprehensive characterization of SVD allowed us to differentiate between two different SVD subtypes: hypertensive arteriopathy and cerebral amyloid angiopathy SVD. Importantly, we observed that the two SVD subtypes were differentially related to Alzheimer’s disease pathologies and risk factors. Specifically, neuroinflammation and modifiable risk factors were more closely associated with hypertensive arteriopathy, while amyloid and tau related more closely to cerebral amyloid angiopathy.
What made you want to do a PhD?
The most challenging part was figuring out what I wanted to do with my life. Once I realised that the problem of dementia was one that I cared about (at both an emotional and intellectual level), I started thinking about how I could contribute the most. This didn’t lead me directly into neuroscience research, though. It took some calibration to get my directions right. In my first job, working on healthcare policy research in the Singapore government, I realised that our ability to make good policy decisions was limited by how little we knew about dementia. Since I was already intrinsically passionate about neuroscience and brain health, I started planning a new path to contribute to dementia research. Step 1 was restarting my career to accumulate experience as a Research Assistant, which was much more difficult than it sounds. Step 2 was getting a PhD to qualify me to lead independent research, representing the most enjoyable role I’ve ever held. Now that that’s over, I guess that brings me to Step 3 – doing a postdoc while preparing fellowship applications.
Doing a PhD was never part of my plan growing up. It was probably the furthest thing from my mind. But as I started to develop an overarching life plan, the PhD became a natural step and a thoroughly enjoyable one.
What was your best day during your PhD?
That’s a tough one. There are so many to choose from! Some of my happiest and most salient PhD memories come from seemingly ordinary days in the lab conducting analyses and bouncing off the enthusiasm of fellow lab mates, discussing ideas, the latest software and methods, or our exciting new results, or presenting my work and receiving fantastic advice, some random lab drinks, the day of my viva, etc.
I wish I could tell you about them, but if I were forced to choose just one day, I would say 2 March 2022 at the Alzheimer’s Research UK Conference 2022. That was the first time I attended a conference *in person* since the pandemic began – and this was also the first in-person presentation of my PhD. By that point, I’d done several online presentations, but presenting to a room full of people was a completely different experience. The instantaneous feedback of nods, eye contact, laughter etc, was a real source of encouragement and things I will never take for granted again. It was an exhilarating and completely enjoyable experience. Thankfully, the talk was well-received too. Having people tell me they enjoyed the presentation reassured me that it was worth the extra effort I put in to communicate my research clearly and effectively. Extending from that, the conference also gave rise to new opportunities and connections, which have enriched my PhD in various ways.
What was your worst day during your PhD?
Incidentally, also 2 March 2022. While waiting for the train home from the conference, I rummaged through my bag and dropped my external hard drive. I lost a bunch of data I was processing (raw data were safely backed up in the cloud, thankfully). That hard drive is now a brick, with no function other than producing whirring sounds and a deceptive green light.
Do you have any advice for future PhD/MPhil students in Psychiatry?
- Be clear on why you’re doing your PhD. Having that clarity has really helped me sustain my drive and willpower, especially on days I’m stuck doing certain aspects of research I don’t enjoy. On such days, it helps to remind myself that although some of the work may not be personally beneficial, it ultimately contributes to advancing our understanding of dementia. That keeps me going.
Don’t underestimate the importance of a good supervisor and lab mates. You have probably heard this ad nauseam by now, but I can’t in good conscience not emphasize this when given a chance. I had the privilege of having not one but two fantastic supervisors. They gave me so much freedom and support to study the things I was interested in and were very receptive to my support needs. On top of that, I had colleagues who were always willing to help. They were excellent sounding boards for ideas and generally great people to have in my life. I think that played a huge role in making my PhD as enjoyable as it was, and I’ve learned that this was a privilege I should never take for granted.
Know when to ask for help. I take a little too much pride in being independent. I often spent too long struggling with something alone before I had the courage (and humility) to ask for help. But when I do, people are generally very helpful, and I could have saved so much time if I had only approached them earlier. Very importantly, remember the help you have received, and when you have the chance, do pay it forward.
For the sake of future you, record EVERYTHING. I use Evernote to record everything I do, e.g., commands I ran, folders I renamed, items I moved, etc. All with timestamps and colour-coding. It saves me so much time when I inevitably have to revisit a project I did in the past. Now I use Git too, which makes version control so much more seamless.
What do you hope to do next?
Shortly after submitting my thesis, I started a new role as a postdoctoral researcher in the Department of Clinical Neurosciences, where I am approaching the same broad research aim but from a different angle. Specifically, I’m furthering my work by looking deeper at how inflammation and the blood-brain barrier play a role in cerebral small vessel disease.
And currently, I am preparing my first fellowship application to investigate specific biomarkers of cerebrovascular disease in dementia. Hopefully, I’ll have good news to share soon. Fingers crossed!