Alzheimer's Disease

Background

Clinical KeyAlzheimer’s disease (AD) is a progressive neurodegenerative brain disease which attacks the neurons in the brain, leading to cell death and degeneration. Early symptoms of the disease include memory loss and confusion and can progress to disorientation, personality changes, and trouble speaking and writing. AD is the most common cause of dementia, with over 5 million people affected in the US. The prevalence of AD in the US is expected to be 13 million in 2050, with a cost of over 1 trillion dollars.

The symptoms are deficits in multiple cognitive domains, with evidence of aphasia, apraxia, agnosia and reduced executive functioning. Declarative memory deficits are early features, followed by more widespread memory decline and general functional reductions due to widespread cognitive deficits.

The disease manifests as two different types of lesions in the brain: Beta-amyloid plaques – clumps of protein that form on and around the neurons; and Neurofibrillary tangles – twisted fibers of the protein, tau, which build up inside the neurons. Although these are the hallmarks of the disease, scientists do not know why they form or how to get rid of them.

Current Treatment

DeKosky Webinar Graphic 300

There is currently no cure for Alzheimer’s. However, there are various medications that can delay the progression of the disease. Treatment must be constantly monitored and adjusted because the symptoms of Alzheimer’s change as the disease progresses.

The current mainstay of care is medical treatment focused on enhancing the activity of acetylcholine (Ach), by preventing its breakdown with medicines. This inhibition prevents the normal breakdown of Ach, and is a way of compensating for the lowered levels of Ach in Alzheimers. The use of these drugs have improved memory and language deficits in early disease, but are less effective in later stages of the disease. Another drug, Memantine, has shown modest benefits in reduction of cognitive declines in moderate to severe AD cases, but no significant history on the natural history has been proven. Side effects are an issue with the above drugs, including fatigue, vomiting, loss of appetite and headache.

Another area of research focuses on the administration of antibodies that can directly attack amyloid and tau proteins. The challenge with antibody treatment however is the size of these molecules and their inability to efficiently cross the blood brain barrier (BBB). The BBB prevents the passage of large, molecules from the blood stream in to brain tissue, and as a result, limits the delivery of potentially therapeutic compounds, including antibodies, stem cells, gene therapy, amyloid cleaving enzymes, and growth factors.

Other medications can be prescribed specifically to manage the symptoms associated with Alzheimer’s. Antidepressants can help with depression, anxiolytics can aid in managing anxiety, and antipsychotics can treat hallucinations and aggression.

Focused Ultrasound

Focused ultrasound (FUS) has been proven to be an attractive modality for non-invasive thermal ablation of soft tissue virtually anywhere in the body. FUS involves the application of acoustic energy at high frequencies from over 1000 individual transducers onto distinct body targets.

At low frequencies, and in conjunction with injected microbubbles, FUS is able to temporarily open the BBB to permit passage of large molecules that would otherwise be unable to pass. This was first accomplished at Sunnybrook Hospital in Toronto, Ontario, in the context of BBB opening for high grade brain tumors. The ability to temporarily open the BBB could open the use of FUS to aid in any situation where crossing the BBB is needed, including brain tumors, AD, and other neurodegenerations associated with protein misfolding.

For high frequency uses, the target region of the body has temperature elevation, which is responsible for the ablation of the target tissue. In low frequency FUS, there is no appreciable increase in temperature. The targets can be larger, so that optimally the entire region for BBB opening can be included in the desired treatment region. Post sonication injection with gadolinium contrast can delineate the areas of opening of the BBB, and therefore drug enhancement.

There is a study opening at Sunnybrook Hospital in Toronto, Canada, which will use low frequency FUS to temporarily open the BBB in patients with mild to moderate AD. This early-stage study will be designed to assess the safety, feasibility and reversibility of BBB opening as well as the reproducibility of repeated BBB opening in human patients. This study is only open to Canadian residents. For more information, please contact Alison Bethune ( or 416-480-6100 ext.3773)

Another area of research is exploring the potential for focused ultrasound alone to stimulate neuronal activity in Alzheimer’s disease and other neurodegenerative diseases. However, this field of research is still in its infancy.

Notable Papers

Burgess A, Hynynen K. Microbubble-Assisted Ultrasound for Drug Delivery in the Brain and Central Nervous System. Adv Exp Med Biol. 2016;880:293-308. doi: 10.1007/978-3-319-22536-4_16.

Focused Ultrasound for Alzheimer's Workshop Summary - September 2015

Meairs S. Facilitation of Drug Transport across the Blood-Brain Barrier with Ultrasound and Microbubbles. Pharmaceutics. 2015 Aug 31;7(3):275-93. doi: 10.3390/pharmaceutics7030275.

Leinenga G and Götz J. Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model. Sci. Transl. Med. 2015;7:278ra33.

Burgess A, Dubey S, Yeung S, Hough O, Eterman N, Aubert I, Hynynen K. Alzheimer Disease in a Mouse Model: MR Imaging-guided Focused Ultrasound Targeted to the Hippocampus Opens the Blood-Brain Barrier and Improves Pathologic Abnormalities and Behavior. Radiology. 2014 Dec;273(3):736-45.

Burgess A, Hynynen K. Noninvasive and targeted drug delivery to the brain using focused ultrasound. ACS Chem Neurosci. 2013 Apr 17;4(4):519-26.

Burgess A, Aubert I, Hynynen K. Focused ultrasound: crossing barriers to treat Alzheimer’s disease. Ther Deliv. 2011;2(3):281-6.

Click here for additional references from PubMed.

     

Share this page