Parkinson’s Disease (PD) is a neurodegenerative brain disease that is progressively debilitating and leads to motor dysfunction and cognitive decline. PD affects more than 10 million people worldwide and nearly 1 million in the US. Healthcare costs in the US alone related to PD are estimated at $52 billion per year.
PD is caused by degeneration of “dopamine neurons” that reside predominantly in a location of the midbrain called the substantia nigra. These neurons project to other areas within the brain and normally work to promote smooth, effective motor function. With the loss of dopamine neurons caused by PD, these pathways are disrupted, leading to a slowing of voluntary movements (bradykinesia and rigidity) and increased involuntary movements (tremor and dyskinesia).
Another hallmark of PD is an abnormal accumulation of a protein called alpha-synuclein, which can become misfolded and aggregate into clumps within the brain. It is thought that these abnormal deposits of alpha-synuclein play a role in the pathophysiology of PD, but the exact mechanism is unknown.
Scientists believe that there are several environmental and genetic factors that cause PD. Interestingly, PD is a very diverse disorder in its physical manifestations — no two individuals will present with the same symptoms. There are three main subtypes of motor symptoms: 1) Tremor-dominant, meaning patients experience more tremor than any other motor symptoms, 2) Akinetic-rigid, where patients exhibit slowness of movement accompanied by muscle stiffness and postural/gait instability, and 3) Not determined, in which patients show mixed symptoms.
The most widely used treatments for PD are medications that focus on reducing motor and cognitive symptoms. Surgical treatment options are available for patients who have exhausted medical therapies or who suffer from medication-induced dyskinesia or profound motor fluctuations. The goal of current surgical treatment options is to inhibit specific regions and movement pathways within the brain to control motor symptoms. Deep brain stimulation has become the preferred surgical method over invasive surgical ablation techniques, but it is also invasive and requires implantation of hardware in the brain and repetitive surgeries. More recently, focused ultrasound has begun to offer a noninvasive ablative therapy for PD that has been shown to be safe and effective. Additionally, focused ultrasound is being studied to not only treat the symptoms of PD but potentially treat the underlying cause of the disease as well.
Clinical Trial Update: Treating Parkinson’s with Focused Ultrasound
Focused Ultrasound to Treat the Symptoms of Parkinson’s Disease
Focused ultrasound has international and FDA approval to treat tremor-dominant PD, a form of PD in which the predominant symptom is tremor. The use and eventual approval for this treatment came on the heels of the approvals for focused ultrasound to treat essential tremor, because the target – a brain structure called the ventral intermediate nucleus of the thalamus – is identical in both diseases. This focused ultrasound ablation treatment is now gaining reimbursement success.
Focused ultrasound is also being assessed to treat Parkinson’s dyskinesia, which is characterized by uncontrolled, involuntary movements of the face, arms, legs, or trunk. To date, pilot clinical trials have demonstrated safety and efficacy of focused ultrasound ablation of three brain targets for the treatment of PD dyskinesia: the internal section of the globus pallidus, the subthalamic nucleus, and the pallidothalamic tract.
In all of these clinical trials, patients were shown to have improvements in their global rating scores for motor disability while experiencing no serious adverse events. As with any brain treatment, there were some side effects, but most of these were transient and resolved over time.
After the initial pilot clinical trial involving the internal section of the globus pallidus was completed, a pivotal multi-center clinical trial including over 90 PD patients was fully enrolled. The follow-up is now occurring, and results are expected to be available by the end of this year.
Furthermore, focused ultrasound has the potential to treat the cognitive impairment associated with PD. A study conducted in Madrid, Spain, used focused ultrasound to temporarily open the blood-brain barrier (BBB) in the parieto-occipital-temporal cortex. The tight junctions of the BBB are designed to be an extra protection to the brain, but it also limits the ability of therapeutics to access the brain. This temporary opening may allow toxic metabolites to depart from the brain and also may enable therapeutics to enter the desired area of the brain. The procedure was shown to be safe and effective, and some patients experienced an improvement in cognitive testing. Of note, these results are still early, and additional information will continue to be gathered.
Focused Ultrasound to Treat the Underlying Cause of PD
Focused ultrasound-induced BBB opening and subsequent delivery of therapeutics may also have the potential to curb, or even reverse, the progression of PD.
A groundbreaking clinical trial out of Sunnybrook Health Sciences Centre and University Health Network in Toronto, focused ultrasound BBB-opening of the putamen is being used in combination with an enzyme replacement therapy called imiglucerase (Cerezyme) for patients who have PD and a deficiency of a naturally occurring enzyme called glucocerebrosidase. After proving the initial safety and efficacy of this technique, the hypothesis is that the BBB opening will allow the therapeutic to be effectively delivered to this area of the brain where it will hopefully improve the metabolic pathway and possibly lessen the impacts of PD.
In another pilot trial in Spain, from which results are pending, focused ultrasound was used to safely and temporarily open the BBB in an area of the brain called the putamen, in hopes that future trials can enhance drug delivery to this region and increase dopamine levels.
Preclinical Research Update
The Focused Ultrasound Foundation is funding several preclinical laboratory studies to investigate focused ultrasound’s ability to safely and temporarily open the blood-brain barrier (BBB) and improve the delivery of various neurotherapeutics, including genes, stem cells, growth factors, neuroprotective and neurorestorative drugs, and anti-alpha synuclein antibodies. These therapies have been shown to slow the progression of Parkinson’s disease, halt the degeneration of nerves within the brain, or promote healthy nerve tissue regeneration.
The following is a list of recent Focused Ultrasound Foundation–funded preclinical PD research projects:
MR-guided Focused Ultrasound BBB Drug Delivery with adeno-associated virus 2 Gene Therapy Microbubble Drug Conjugates
Sunnybrook Health Sciences Centre
Antibody Delivery through the BBB Opening in an Alpha-Synuclein Model
Columbia University
MR-guided Focused Ultrasound Gene Delivery for Neuroprotection in PD
Weill Cornell Medical Center
Minimally Invasive Therapy for PD Achieved by the Focused Ultrasound-Targeted Delivery of Gene-Bearing Nanocarriers
Johns Hopkins University School of Medicine
Focused Ultrasound for Increased Delivery of Intranasal DNA Nanoparticles to Rat Brain
Northeastern