Separating Early AD and Aging Effects in Search of Markers to Track Alzheimer’s Treatment Effects

Laura Wisse, PhD
University of Pennsylvania (Philadelphia, PA)

Mentors

David Wolk, MD, PhD
University of Pennsylvania
Paul Yushkevich, PhD
University of Pennsylvania
Year Awarded:
2016
Grant Duration:
July 1, 2016 to January 30, 2019
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2016432F
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern

This grant is made possible in part by a bequest from the Trust of Elenore Lundeen.

Laura Wisse, PhD

The Medial Temporal Lobe in Preclinical Alzheimer’s Disease and Aging

Summary

Drug trials are increasingly being started in an early stage of Alzheimer’s disease (AD), before memory problems start. This is an attempt to intervene before brain damage becomes too severe. To test how well such treatments are working, we need a good measure that can track various treatment effects in the brain. A good candidate for assessment is the brain region known as the medial temporal lobe (MTL), because it is affected in an early stage of AD. However, a fact that complicates using the MTL as a marker is that this brain region is also affected in normal aging. To separate the effects of preclinical AD from normal aging, we plan to investigate the MTL with an extremely precise, high resolution magnetic resonance imaging scanner. This will allow us to investigate smaller regions within this brain region which has an advantage over cruder measurements and methodologies in that it is expected to show differential effects of aging and preclinical AD.

Details

I am interested in studying atrophy (shrinking) of small regions within a part of the brain called the medial temporal lobe (MTL) in an early stage of Alzheimer’s disease (AD). This brain region is affected early in the course of AD and measurements in this region might therefore generate a valuable biomarker to track disease progression and test the effectiveness of a new treatment.

I am investigating this in three steps. In the first step, I investigate which subregions of the MTL are affected in a very early stage of AD, and which by aging processes. Characterizing this helps with finding a subregion that shrinks only because of AD, and not because of normal age-related processes, and will therefore be a good biomarker for AD. I am investigating this in a group of older adults, some of whom have plaques (eg, amyloid deposition) considered to indicate the presence of AD. Both groups are scanned with a new MRI scanner that allows for fine-grained measurements of the MTL. We determine which subregions of the MTL are affected in AD, and which are affected by aging, by comparing the size of these regions in both groups and relating the size with age.  In the second part we further investigate what processes, besides the mentioned AD pathology, affect these regions. We investigate, for example, the role of vascular damage in the brain using measurements on MR images and the role of certain genes that give an increased risk of AD. Understanding the influence of these factors helps determine who is most apt to benefit most from a treatment, and it also might generate new treatment possibilities. A third step is to understand which memory problems result from damage to these regions in the MTL. The different regions that make up the MTL are thought to be responsible for the different aspects of memory. For example, one region may be responsible for saving new information, whereas another may be responsible for recalling information. All subjects in the study will undergo several memory tests and their performance will be related to the size of the MTL regions.

What is novel about this study is that we investigate these questions in persons who do not yet have any symptoms. Investigating in an early stage is important because treatment in an early stage could prevent brain damage. A second important aspect is that we use the newest imaging techniques to obtain very precise measurements, which are hypothesized to be better at identifying AD than the current, coarser measurements of this brain region. Another important aspect is that we investigate a number of other factors, including genes and pathologies that could affect this brain region.

My ultimate goal is to find a good biomarker in the brain that can help track disease progression and treatment effects in an early stage of the disease, before the damage has become too severe.  This marker can then be used to help evaluate new treatments that are being developed and will help treat or prevent AD. The big advantage of the type of biomarkers to be generated in this project is that they can be obtained by MRI, which is relatively cheap and non-invasive, and therefore is widely accessible. Additionally, understanding what processes, besides AD, lead to shrinkage in this brain region may also lead to other interventions, and may lead to better understanding of memory impairments not only in aging and AD, but also related diseases, such as depression.

About the Researcher

Laura Wisse obtained her master’s degree in clinical neuropsychology in 2010, at Leiden University, the Netherlands. During her master’s program, she did a clinical internship at the Geriatrics Department of Medical Center Alkmaar, the Netherlands, where she learned to perform cognitive testing, part of the diagnostic process for patients with memory and other cognitive complaints. In January 2011, she started her PhD studies at Utrecht University Medical Center in the Netherlands, focusing on ultra-high resolution imaging of the brain. She focused on the hippocampus, a brain region of great importance for memory and therefore also of importance for aging and disease. Laura developed a new method to measure smaller regions within the hippocampus to study this brain region in more detail and learn more about the effects of aging, Alzheimer’s disease (AD), and depression on these regions. After her PhD studies, Laura became a postdoctoral fellow at the University of Pennsylvania with Dr. David Wolk and Dr. Paul Yushkevich. She continues her work on improving methods to measure these small regions of the hippocampus and studying brain changes in aging and AD.

Personal Story

I learned about dementia during high school, as part of my weekend job as a nurse assistant at an elderly care center. For several years I worked at this daycare facility for patients with dementia. I loved working there, talking with the patients, and arranging activities. Although from time to time it was devastating to see the impact of dementia on a person and their family, I was able to provide some relief on a day-to-day basis by talking about their loved ones, playing games, listening to music from the patients’ childhood, etc.

From this background, I went to university to study psychology and got my master’s degree in clinical neuropsychology. During my internship, at a geriatrics department, which was part of my Master’s program, I got to see an earlier stage of the disease than at the elderly care center. People would come in worried about their memory performance. Although sometimes I could bring good news, in general, I felt that as a neuropsychologist I couldn’t do a lot for these people by diagnosing them with a disease for which little treatment is available.

These experiences reinforced my decision to go into science and do brain research in aging and dementia, which I’m continuing now in Philadelphia. I am really motivated to contribute to the understanding of how Alzheimer’s disease affects the brain and, ultimately, to find a good marker to track disease progression, one that also, by pinpointing early areas of decline, will help with the development of a treatment. Without the Brightfocus Fellowship, this work would not have been possible.

Publications

de Flores R, Berron D, Ding SL, Ittyerah R, Pluta JB, Xie L, Adler DH, Robinson JL, Schuck T, Trojanowski JQ, Grossman M, Liu W, Pickup S, Das SR, Wolk DA, Yushkevich PA, Wisse LEM. Characterization of hippocampal subfields using ex vivo MRI and histology data: Lessons for in vivo segmentation. Hippocampus. 2019 Nov 1. doi: 10.1002/hipo.23172. [Epub ahead of print] PubMed PMID: 31675165. PubMed Icon Google Scholar Icon

Das SR, Xie L, Wisse LEM, Vergnet N, Ittyerah R, Cui S, Yushkevich PA, Wolk DA; Alzheimer's Disease Neuroimaging Initiative. In vivo measures of tau burden are associated with atrophy in early Braak stage medial temporal lobe regions in amyloid-negative individuals. Alzheimers Dement. 2019 Sep 5. pii: S1552-5260(19)30150-5. doi: 10.1016/j.jalz.2019.05.009. [Epub ahead of print] PubMed PMID: 31495603 PubMed Icon Google Scholar Icon

Xie, L., Wisse, L. E., Pluta, J., de Flores, R., Piskin, V., Manjón, J. V., ... & Yushkevich, P. A. Automated segmentation of medial temporal lobe subregions on in vivo T1‐weighted MRI in early stages of Alzheimer's disease. Human Brain Mapping. PMID: 31034738 DOI: 10.1002/hbm.24607 PubMed Icon Google Scholar Icon

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