Simon Laganiere, Beth Israel Deaconess Hospital, Massachusetts, Mentor Dr. Sam Frank
Identifying novel neuroimaging biomarkers in early pre-manifest Huntington’s disease
Although genetic testing can reveal whether Huntington’s disease will develop, it cannot reliably predict when symptoms will begin. As a result, deciding when to administer new treatment strategies through clinical trials will remain challenging. In other words, testing a potential new treatment too early or too late may fail to impact disease progression. Therefore, we need more accurate models of disease onset and progression in HD. Recently, innovative brain imaging methods have been used to look at brain function through the lens of interactions between brain networks. These methods have started revealing early changes prior to the start of clinical HD symptoms. This proposal seeks to study presymptomatic individuals to better understand how specific brain networks interact during challenging cognitive tasks. Combining specific tasks with simultaneous brain imaging constitutes a type of cognitive stress test that will show brain changes earlier than they would otherwise appear. If successful, results from this study will help determine the optimal timing for eventual disease modifying treatments.
Bjoern von Einem, Ulm University, Germany, Mentor Dr. Bernhard Landwehrmeyer
Feasibility of assessing mHTT and wtHTT mRNA levels in CSF-derived exosomes
A new type of drug to treat Huntington’s disease, called an antisense oligonucleotide (ASO), is the first treatment that may actually slow down HD’s relentless progression. ASOs are short pieces of man-made genetic material that interact with the product (RNA) of huntingtin, the gene mutated in Huntington’s disease. This interaction leads to destruction of the RNA and ultimately reduces the amount of Huntingtin protein in a patient. The newest types of ASOs focus on reducing harmful huntingtin while leaving the healthy form intact. The challenge now is to monitor the effectiveness of these ASOs, by sampling the fluid that surrounds the brain and spinal cord. The cells of the brain release tiny bits of themselves, called exosomes, which should reflect what is going on in the brain cells from which they are released. Developing the technology to use exosomes for measuring huntingtin will allow researchers to monitor the effects of ASO drugs less invasively. In summary, the goal of this project is to find a technique to use spinal fluid for a view into the brain to guide development of innovative and effective treatments of Huntington’s disease.
Yifat Glikmann-Johnston, Monash University, Australia, Mentor Dr. Julie Stout
Targeting the Huntington’s disease gut microbiome
Recent research in neuroscience has shown that the gut communicates with the brain via a two-way system called the gut-brain axis. Increasing evidence shows that the balance of bacteria in the gut can actually influence brain functions like sleep, mood, thinking, and memory. In Parkinson’s disease this imbalance can worsen movement symptoms. In HD, we know that gastrointestinal problems are common, and many patients experience extreme weight loss, diarrhea, and gastritis. However, most of what we know about gut bacteria in HD comes from mouse studies. This group has recently shown the first evidence of bacterial imbalance in the gut of people with HD. They now propose to carry out a large study to understand the key differences in gut bacteria between people with and without the HD gene. This foundational work will serve to determine whether there is a relationship between the complex world of microbiota in our intestines, and brain function and disease progression in people with HD, with a focus on mood and cognition. The gut may be a suitable marker of disease, and an excellent target for drug development and non-pharmaceutical interventions.
Melanie Alpaugh, Laval University, Canada, Mentor Dr. Francesca Cicchetti
Interrogating blood samples from Huntington’s disease patients to better understand cognitive impairments
Cognitive decline is a major clinical symptom of Huntington’s disease (HD), which often appears early in disease and inevitably impacts the patient’s quality of life. However, there are currently no reliable tools to predict which individuals are likely to develop cognitive deficits. Identification of factors in the blood that can be used to track such symptoms would have important implications for clinical trials as well as symptom management. In this study, we propose to investigate various elements of the blood to determine if they may be able to serve as a predictor of vulnerability to cognitive deficits. First, we will evaluate tau, a protein present in brain cells that helps maintain their internal skeleton. In several brain disorders, tau aggregates in clumps and impairs neuronal function. Tau has a well-described role in Alzheimer’s disease, however, other disorders such has Parkinson’s disease and HD have also been described to have tau pathology. The commonality of tau pathology to multiple nervous system disorders presenting with cognitive decline suggests that the presence of tau may contribute to this aspect of disease. Further evidence of this relationship in HD comes from studies demonstrating that different versions of the tau gene correlate with cognitive decline and its severity in patients. Aside from tau, we plan to isolate extracellular vesicles, small structures that carry information/messages between cells. Vesicles are interesting as they move readily between the brain and the blood, meaning that we can use vesicles found in the blood as a window into the health of brain cells. By exploring one specific and one more general marker of neuronal health, we aim to both identify novel indicators and to increase our understanding of which neuronal changes relate to the development of cognitive impairments.