Disrupted neural activity patterns to novelty and effort in young adult APOE-e4 carriers performing a subsequent memory task

Introduction

The APOE e4 allele has been linked to poorer cognitive aging and enhanced dementia risk. Previous imaging studies have used subsequent memory paradigms to probe hippocampal function in e4 carriers across the age range, and evidence suggests a pattern of hippocampal overactivation in young adult e4 carriers.

Methods

In this study, we employed a word-based subsequent memory task under fMRI; pupillometry data were also acquired as an index of cognitive effort. Participants (26 non-e4 carriers and 28 e4 carriers) performed an incidental encoding task (presented as word categorization), followed by a surprise old/new recognition task after a 40 minute delay.

Results

In e4 carriers only, subsequently remembered words were linked to increased hippocampal activity. Across all participants, increased pupil diameter differentiated subsequently remembered from forgotten words, and neural activity covaried with pupil diameter in cuneus and precuneus. These effects were weaker in e4 carriers, and e4 carriers did not show greater pupil diameter to remembered words. In the recognition phase, genotype status also modulated hippocampal activity: here, however, e4 carriers failed to show the conventional pattern of greater hippocampal activity to novel words.

Conclusions

Overall, neural activity changes were unstable in e4 carriers, failed to respond to novelty, and did not link strongly to cognitive effort, as indexed by pupil diameter. This provides further evidence of abnormal hippocampal recruitment in young adult e4 carriers, manifesting as both up and downregulation of neural activity, in the absence of behavioral performance differences.

 

Evans, S.Dowell, N. G.Tabet, N.King, S. L.Hutton, S. B. and Rusted, J. M. (2016), Disrupted neural activity patterns to novelty and effort in young adult APOE-e4 carriers performing a subsequent memory taskBrain and Behavior00111. e00612, doi: 10.1002/brb3.612

For full access to the paper click here

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Doing a PhD in the Alzheimer’s Society Doctoral Training Centre at Sussex –being part of a team and enjoying it!

DTC-74

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The Elusive Nature of APOE ε4 in Mid-adulthood: Understanding the Cognitive Profile

Objectives: The apolipoprotein E (APOE) ε4 allele is an established risk factor for dementia, yet this genetic variant is associated with a mixed cognitive profile across the lifespan. This study undertakes both a systematic and meta-analytic review of research investigating APOE-related differences in cognition in mid-adulthood, when detrimental effects of the allele may first be detectable.

Methods: Thirty-six papers investigating the behavioral effects of APOE ε4 in mid-adulthood (defined as a mean sample age between 35 and 60 years) were reviewed. In addition, the effect of carrying an ε4 allele on individual cognitive domains was assessed in separate meta-analyses.

Results: The average effect size of APOE ε4 status was non-significant across cognitive domains. Further consideration of genotype effects indicates preclinical effects of APOE ε4 may be observable in memory and executive functioning.

Conclusions: The cognitive profile of APOE ε4 carriers at mid-age remains elusive. Although there is support for comparable performance by ε4 and non-e4 carriers in the 5th decade, studies administering sensitive cognitive paradigms indicate a more nuanced profile of cognitive differences. Methodological issues in this field preclude strong conclusions, which future research must address, as well as considering the influence of further vulnerability factors on genotype effects.

Lancaster, C., Tabet, N., & Rusted, J. (2016). The Elusive Nature of APOE ε4 in Mid-adulthood: Understanding the Cognitive Profile. Journal of the International Neuropsychological Society, 1-15.

For full online access to the article click here

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5 Tips from a Thesis Writing Boot Camp

Right before the holiday season, I decided to attend the Sussex University Doctoral School’s Thesis Boot Camp and was pleasantly surprised by how much I accomplished and learned. One limitation was that the writing workshops mostly catered to the humanities so, in addition to sharing top tips, I’ll also be translating the strategies (on the fly) for us psych folk. I’ll also note how the strategies differ from (incorrect) implicit assumptions I’ve held:
  1. Develop a routine that works for you, specifically: I’ve held onto the implicit assumption that there is a “right” way to do a PhD despite my supervisors and classmates telling me no. Despite this, I know there are others like me comparing themselves to other doctoral students and subsequently, feeling inferior. At thesis boot camp, we were encouraged to figure out what works for us
  2. Try and remove any psychological barriers between you and your writing: …No one at boot camp actually said that, but I think it summarizes what Liz was trying to get across. Specifically: writing is a form of thinking. It’s difficult to form an argument until you start writing so “shut up and write!” That being said, the reason we were told previous attendees wrote as many as 20,000 words in one weekend was because it was “first draft material” or what I refer to as my “messy outline.” As we all know,  psychology articles tend to be pretty information-dense; thus, I knew that if I was going to get anything out of this intensive writing weekend, I needed to bring along some version of my messy outline and then write from that. I also spent half a day editing what I’d already written. Thus, I “only” managed to write 6,000ish words, but I still felt pretty proud of myself (for the most part).
  3. On the subject of editing, dont edit while you write: Something I found REALLY helpful was the notion that multi-taking while writing is not time- or cognitively-efficient. This idea might seem like common sense, but if you’re anything like me, you rarely listen to logic when it comes to writing well, because writing a thesis is stress-inducing. Well, because the boot camp was only two days, I thought I might as well give this logical notion a whirl and by George, it worked! When I was writing content, I only let myself make tiny edits on the sentence I’d just written (because that’s how I write), and I’d try not to let myself go back and read what I just wrote (my worst, self-induced time-suck). After that, I’d only let myself do organization, content-based edits (we were encouraged to break down the process of editing into distinguishable tasks), etc and then, when I was happy with what I was trying to say, I’d copyedit.
  4. Collect evidence based on facts, not emotions: we were encouraged to try out the pomodoro technique (25 mins on, 5 mins break x 3, 25 mins on, long break – REPEAT) for the morning of the first break. Liz encouraged us to base our daily/weekly goals on how much work you achieve on average during one pomodoro in addition to how many pomodoros you can realistically do in a day. I know that at least for me, if I’m feeling particularly motivated, I’ll set myself a word-count goal that is way to high. The only issue with this is that I end up disappointing myself rather feeling accomplished by the end of the day.
  5. If your time management/organization method stresses you out, find/make a new one: If you’re anything like me, getting through your doctorate is a mind-warp (in lieu of a different phrase). Not only is the work challenging, but, because we’re often not credited for how difficult it is to go from dependent undergrad (or whatever) to independent, kickass researcher, we end up feeling inferior to our classmates. I think this is a mind-game that more PhD students would benefit from tackling. There is no right way to do a PhD and thus, there is no right way to organize your time! 
I have more notes from what I learned at Thesis Boot Camp but not enough time to write all of them up (this girl has got to finish her thesis). That being said, if you’re keen to hear more of my ramblings, I’d love to go for a coffee. If you know me, you know I’m pretty chatty. My email is m.berenhaus@gmail.com.
Molly Berenhaus
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Dementia in the clinic

One of my PhD colleagues, Rebecca Atkinson, wrote recently that each student at Sussex funded by the Alzheimer’s Society charity is afforded the opportunity to complete placements in a local Memory Assessment Services (MAS) clinic. I was paired with Consultant Psychiatrist Dr Cathy Ulliott, who specialises in old age psychiatry, and have attended the outpatient centre in Shoreham twice since May.

On my first visit, I met with Cathy to discuss the process that patients in this area of Sussex experience when they are referred to the MAS team. In different NHS regions, the practice can differ, but in the local Sussex area, patients will be referred by their GP to the MAS team, and first contact is typically with a specialist nurse, with whom the patient will complete a number of assessments including the ACE (Addenbrookes Cognitive Examination). The patient will typically also have a brain scan. Together, assessments such as these help the clinician build a picture of a person’s performance in cognitive domains of language, spatial ability, problem solving, and aspects of memory, alongside being able to determine whether any damage, degeneration, or reduced vascular supply is evident in the brain.

On my second visit, I attended Dr Ulliott’s clinic, in which she met with three patients. The primary role of these appointments was to establish a diagnosis for each individual, based upon the results of the assessments, in combination with information on the individual’s family and medical histories, and interviews with the patient and their carer(s) in terms of how their cognitive difficulties might be presenting in their everyday life. Following diagnoses and administration of treatment (where possible and appropriate), patients would meet with the Dementia Advisor on-site, who is employed by the Alzheimer’s Society. The Dementia Advisor is able to help the patient and their carer navigate Social Services’ Care Needs Assessments, give information on the different types of dementia, and provide materials and contacts for social and professional support available in the local area.

The patients I observed were aged between 78-82, two male and one female; all three patients were given diagnoses of mixed dementia, vascular dementia with Alzheimer’s. What struck me most keenly during my observation of the sessions however, was the difference between each of these patients’ abilities despite receiving the same diagnosis, and being of similar ages. Differences were noticeable in terms of the patients’ capacity to recognise and articulate their abilities and limitations, and the reports from the caregivers accompanying the patient (in all three cases, the patient’s spouse), but most surprising to me was the differences that were evident in each individual’s ability to perform in the memory assessment tests, and the extent their problems affected their completion of everyday tasks and ability to live a full life.

The differences between each of the patients I saw in Dr Ulliott’s clinic brought home to me the extent to which other aspects of health can affect the subjective patient experience of having dementia, as well as the way in which individual differences and life experiences may affect both the personal experience and observable development of dementia/cognitive decline at certain stages – an aspect particularly relevant to research being conducted at Sussex.

I was also struck by how difficult it can be to establish accurate diagnoses of the various forms of dementia, and the importance of the expertise and discernment of the Psychiatrist in their analysis not only of the clinical test results, but of the conversations, reporting of symptoms and lifestyle effects of the memory and cognitive problems obtained from the patient and their carer. I found the visit to the MAS clinic extremely informative and look forward to visiting with Dr Ulliott again.

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The APOE paradox: do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline

Possession of an APOE e4 allele is an established risk factor for Alzheimer’s disease, while the less commonly studied e2 variant is premised to offer some protection. This research explores the purported deleterious-protective dichotomy of APOE variants on attentional control in mid-adulthood. 66 volunteers, aged 45-55 years, completed three tasks that provided complementary measures of attentional control: prospective memory, sustained attention and inhibition. Performance was compared between e2 carriers, e4 carriers and e3 homozygotes (the population norm). Carriers of the e4 allele showed subtle disadvantages, compared to the e3 group, in accuracy of Stroop task and prospective memory performance. Contrary to expectations, e2 carriers showed performance disadvantages in sustained attention. The finding of detrimental effects in attentional control for both e4 and e2 complicates the current model that proposes opposing effects of these variants on later-life cognition. Future research is needed to understand how cognitive differences develop with increasing age, and the physiological mechanisms that underpin these changes.

For full online-access to the article click here

Title
The APOE paradox: how do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline
Published in
Neurobiology of Aging
DOI 10.1016/j.neurobiolaging.2016.08.015
Authors

Claire Lancaster, Naji Tabet, Jennifer Rusted

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A clinical perspective: visiting the Memory Assessment Services (II)

In the past months I had the opportunity to shadow Dr. Klugman during two Memory Assessment sessions at the Hill Rise memory clinic in Newhaven. During my short visits there I had the chance to learn more about the process through which patients presenting with symptoms of dementia are diagnosed and how their condition is monitored by the clinic and the doctor. While for other diseases with a more defined aetiology the diagnostic modus operandi are relatively straightforward and defined, when it comes to dementia suddenly everything becomes much more complicated. With my PhD focusing on specific aspects of Alzheimer’s Disease and with a background in neuroscience I was well aware of this situation, however what I learned from these placements is that working on this subject doesn’t necessarily provide you with its full understanding. I was reminded that if the disease, its biology, aetiology, mode of action and origin are one side of the coin, the other side is represented by the people who have to live with this condition and by those who care for them. My first memory clinic was a check up session in which Dr. Klugman encountered patients that had been previously diagnosed and came to the facility to monitor the progress of their condition. It was a routine session that proved insightful in many ways, showing me how the disease affects first of all the person and how this extends to the family and carers, as well as the health system and the society as a whole. The second clinic was, on the other hand, a session in which the doctor met up with new referrals who presented symptoms of dementia but still lacked a complete diagnosis. I was shown how the diagnostic process is not the work of a single practitioner but the joint effort of a team of specialists, how the mixed aetiology of patients presenting symptoms of dementia makes it extremely hard to place them in defined categories and finally how much more effort is needed to fully understand the subject.

Luca Biasetti

My visit at the rehabilitation centre in Newhaven with Dr Osama Hammer was very impressive and gave me the opportunity to experience clinical aspects of dementia. Dr Hammer saw five dementia patients during my visit with varying degrees of the disease (from early to late stages). The different stages of the patients showed me the complexity of the disease and that care and treatment must be personalized for each individual. Dr Hammer was very motivated and took me through all cases. To my positive surprise, he also involved me in some tasks the patients had to perform during their assessment. I also enjoyed our fruitful discussion following the very intense afternoon and Dr Hammer seemed genuinely interested in my opinion of the individual cases. I am looking forward to follow up assessments with these and new patients in the near future.

Lucas Kraft

 

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A clinical perspective: visiting the Memory Assessment Services

As a PhD student, the funding for my studentship comes from the Alzheimer’s Society. This is part of an Alzheimer’s Society Doctoral Training Centre at the University of Sussex, which supports the research of eight PhD students from multiple disciplines over the next 5 years. The Alzheimer’s Society are a charity helping to care for those affected by dementia, and funding research into the cause, cure, care and prevention of dementia.

For more information on the Alzheimer’s society click here.

As part of my studentship, I was offered the opportunity to shadow Dr Naji Tabet at the Crowbrorough memory clinic. Dr Tabet is a long-time collaborator with the Rusted Lab, and has collaborated on a number of research studies so it was nice to get the chance to see Dr Tabet working in a clinical setting.

The patients attending this clinic had already been assessed by NHS memory services, and were attending a follow-up visit to receive further information on their diagnosis and/or advice, treatment and further care provisions. The patients spoke with Dr Tabet with a nurse present, who was often the nurse that conducted a home visit to initially assess the patient, so the patients and family members had a familiar face present.

The patients that attended the clinic on the day I visited had a variety of different outcomes from their initial assessment. Some patients received a diagnosis of Alzheimer’s disease, based on the results of their cognitive tests and brain scans. These patients were offered information about treatment options, and advice about future support. All the patients and family members were pleased to arrange a visit from a dementia adviser, who can guide them in how their individual needs can be supported in the future and in what help is available to them, as well as offering emotional support. Furthermore, they can put patients and their families in touch with local support networks, such as  .

Another individual was attending the clinic because of a family history of Alzheimers. Dr Tabet explained that despite a family of history, it is only a risk factor and does not mean the individual will develop Alzheimer’s disease. Dr Tabet spoke at length how making changes to improve diet, exercise and keep cognitively active could greatly reduce the risk of developing Alzheimer’s disease.

This case was particularly relevant to my PhD, as it related to the genetics of AD, and to reducing risk though changes in the individual’s environment. An individual’s genetic risk of developing the most common type of Alzheimer’s disease is most strongly affected by the APOE gene. The APOE gene has three different alleles (ε2, ε3, and ε4). Carrying the ε4-allele is associated with a higher risk of developing Alzheimer’s disease. Dr Tabet spoke about how environmental changes recommended would be the same regardless of the APOE genotype of the individual. One of the aims of my PhD is to increase our understanding of the interactions between APOE genotype and the environment, which could result in an improvement in our understanding of how to reduce the risk of developing Alzheimer’s disease, and therefore further improve the information that can be given to individuals with high genetic risk for dementia.

By Rebecca Atkinson

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How do genetic risk factors for dementia influence cognition earlier in the lifespan?

We all age, but why do some of us age better than others? This question is especially poignant for the field of cognitive ageing, with the prevalence of dementia rising each year.

At the University of Sussex, the Ageing & Dementia team is exploring the molecular, neural and cognitive mechanisms through which a particular gene – the APOE gene – exerts its influence on cognitive ageing. The APOE gene consists of 3 variants (e2, e3, and e4), of which each person carries a pair (eg. e2e2 or e3e4). Those who carry an e4 variant of the gene have a higher risk for developing Alzheimer’s disease. The gene is also associated with poorer cognitive ageing in healthy adults.

Of interest, the APOE gene is observed to influence cognitive functioning from as early as childhood. Therefore, a crucial avenue of research is exploring how these effects emerge and develop across the lifespan.

We are currently seeking healthy adults aged 18-30 years or 45- 55 years to take part in a research study exploring the influence of APOE variants on our ability to do cognitive tasks that vary in how challenging they are. The study involves a computerized task in which volunteers are required to juggle various cognitive demands in order to succeed. In addition, volunteers will be asked to complete a series of short verbal tasks and questionnaires. Volunteers will also be asked to complete an inner-cheek swab used to determine APOE genotype. We operate under ethical rules that mean neither the participant nor the researcher knows the outcome of the cheek swab. All data will be kept confidential.

If you would be interested in finding out more about the research, please contact claire.lancaster@sussex.ac.uk.

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APOE Symposium

On May 10th, Sussex Doctoral School hosted a symposium recognising the role of Apolipoprotein (APOE) in the development and progression of Alzheimer’s disease. Carrying an APOE e4 gene is established to increase the risk of Alzheimer’s disease in older adulthood, as well as being associated with poorer cognitive ageing in general.

This was an exciting event following the opening of the Alzheimer’s Society Doctoral Training Centre, which is supporting the research of 8 PhD students over the next 5 years.  In addition to a variety of talks and posters throughout the day, focus was placed on promoting public engagement with ongoing research.

On reflection, the day was a huge success, with the following comments made by presenters:

“The symposium featured various fascinating talks from researchers based at Sussex and other UK universities, and a poster session for Sussex PhD students and postdocs. The talks covered a range of subjects, showcasing various avenues of research into the mechanisms by which APOE might influence risk of Alzheimer’s Disease. For example, Prof. Anne-Marie Minihane (University of East Anglia) spoke about how APOE e4 carriers often show higher cholesterol levels in their blood and respond differently to dietary interventions. The quality and breadth of all the research presented was inspiring and the symposium will no doubt lead to increased collaboration between researchers.”

Simon Evans, Post-doctoral researcher

“The APOE symposium was a great day, as it combined interesting academic talks with fun public engagement activities. It was great to see what other people in life sciences and the DTC were doing, and past Sussex PhD graduates. Furthermore, it was a good platform to start presenting work, as most of the DTC students gave flash talks on our PhD projects, and I presented a poster outlining my research plans and early pilot data. “

Rebecca Atkinson- PhD student

POSTER _AS-ARUK Mini-Symposium May 2016 Rebecca copy

Poster presented by Rebecca Atkinson

“To present my project to a non-scientific public was a great experience. The ApoE mini-symposium gave the opportunity to outreach to people and make them aware about the research that is going on at Sussex Uni. But also the scientific talks were very informative and covered a broad spectrum of ApoE research. What I personally enjoyed the most was the informal chat to other PI’s and the chance to discuss their and also my research.”

Lucas Kraft- PhD student

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Poster presented by Lucas Kraft

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Poster presented by Claire Lancaster

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