Brain-wide remodeling after stimulation of the fornix in Alzheimer’s disease – towards improved therapeutic efficacy
University of Toronto, Centre for Addiction and Mental Health
Given the rapidly aging Canadian population, Alzheimer’s disease (AD) is a growing public health concern with few effective therapies available. Most approved and experimental therapies focus on the clearance of a protein known as amyloid. The overproduction and build-up of amyloid over time is thought to be responsible for miscommunication between brain cells and thus result in the cognitive decline observed in patients with AD. However, recent evidence suggests that accumulation of amyloid in the brain reaches an abnormal level well before patients exhibit symptoms of the disease. By the time clinical symptoms of AD are present and followed by a course of treatment, the disease may far too advanced to treat it effectively.
However, recent evidence from animal experiments and a recent clinical trial have demonstrated that direct high-frequency electrical stimulation of memory circuits that are compromised in AD, using a surgical technique called deep brain stimulation, may be an effective treatment for the disease. The therapy involves the surgical implantation of an electrode that provides constant stimulation to specific brain regions that are known to be critical areas affected in AD.
Our project leverages data being collected as part of the multi-centre clinical trial that is testing the effectiveness of deep brain stimulation in AD. This trial is the only one of its kind in the world. Using magnetic resonance images, we propose to identify regions that may be protected against the well-known patterns of brain degeneration in AD. Furthermore, we propose to use the images acquired before deep brain stimulation to determine if we can identify likely responders to this treatment.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Deep brain stimulation was originally pioneered for the treatment of Parkinson’s disease (PD). Since its introduction, approximately 60,000 individuals with PD have received this treatment world-wide and the success rates and effectiveness of the procedure are exceptionally high. The success of deep brain stimulation in this context may be indicative of the potential reach of this procedure and may allow deep brain stimulation to be adopted as an effective method for treating AD.
We believe that the successful completion of this project will allow for the refinement of deep brain stimulation therapies for AD. Furthermore, it will allow us to better understand how memory circuits may be affected by constant electrical stimulation. The successful completion of this project will also demonstrate how deep brain stimulation can be effectively personalized through the selection of prospective candidates based on neuroanatomy. Overall, it will allow for the safe and effective delivery of deep brain stimulation to those AD patients who will derive the greatest benefit both clinically and with respect to quality of life.
Alzheimer’s disease (AD) is quickly becoming one of Canada’s most expensive public health challenges due our rapidly ageing population. The social and economic costs of this progressive brain disease increase substantially with disease severity which are again very much related to age. As populations progressively become older worldwide, many healthcare systems, including Canada’s are on the verge of a significant public health crisis. Effective treatments that could effectively be used to treat or delay onset of AD would have a significant effect on healthcare systems and families and caregivers alike.
Amongst the hallmark clinical symptoms observed in AD is the progressive loss of memory. Within the brain this is further accompanied by progressive degeneration of the parts of the brain responsible for forming new memories; namely the hippocampus. The hippocampus itself is further connected to the rest of the brain via a white matter tract (the wiring in the brain) called the fornix. Our group has recently proposed that this memory system can be “re-activated” using high-frequency electrical deep brain stimulation of the fornix (DBS-f). This technique has been used for decades in the treatment Parkinson’s disease, another neurodegenerative disorder. Further experiments with animal models have recently shown that DBS-f in mice and rats improves memory function and may even promote the generation of new neurons. Therefore, it is possible that DBS-f could improve memory in Alzheimer’s disease by through rearrangement of the brain anatomy itself. Indeed in a trial designed to test the safety of DSB-f in the treatment of AD, we demonstrated that in the first six AD patients to ever receive DBS-f that two patients demonstrated 5-8% hippocampal growth after one year of continuous stimulation. This change in hippocampal volume is completely opposite to what is expected in the natural course of AD.
The findings described above motivated the initiation of a larger multi-‐site clinical trial to test the efficacy of DBS-f. Forty-two AD-patients were enrolled in the trial in several sites throughout Canada and the United States using a unique trial design. The “active” group received continuous stimulation through DBS-f for a year while the “sham” group received only the operation for the implantation of the DBS electrode but it was not turned on and will be turned on after one year. To better understand the effects of DBS-f on brain anatomy we studied the anatomy of the hippocampus using structural magnetic resonance imaging (MRI) in both the groups and had anticipated that the active group would demonstrate preferential bilateral hippocampal growth. Surprisingly, this was not the case: 9/20 patients in the active group demonstrated growth (although the group average was demonstrated very slight decline, -0.7%); while 11/21 patients in the sham group showed growth (group average was 1.4%). We subdivided the group into patients older than 65 as it is commonly thought that those individuals younger than 65 with AD have a very advanced and accelerate form of the disease (14 active and 15 sham remained for analysis). When analyzing this subset we observe that the active group demonstrates 1.0% growth while the sham group demonstrates 1.9% growth. However, if use a complex statistical model that analyzes the rate of change across one year that can account for the differences in site where the patients were scanned and the age of the participants we see that the active group actually demonstrates a significant amount of growth in the right hippocampus relative to the sham group.
Our findings demonstrate two important new pieces of information regarding the use of DBS-f in the treatment of AD. The first is that the implantation of the electrode itself may be inducing rearrangement of the hippocampal anatomy. Further, it is also possible that DBS-f this growth may be further modulated by active stimulation.