In mid-February, the American Parkinson Disease Association (APDA) hosted a panel of researchers who gave updates on their areas of research and the value of research in Parkinson’s disease (PD).  Neurosurgeon Dr. Nicole Bentley and psychiatrist Dr. Daniel Weintraub reviewed deep brain stimulation techniques that improve cognitive symptoms.  Neurologist Dr. Mohammad Shahnawaz and movement disorder specialist Dr. David Standaert explored a blood test that can diagnose Parkinson’s disease.  Biochemist and person with PD Dr. Kevin McFarthing, explained the vital importance of PD research for those living with PD. 

According to Dr. Bentley and Dr. Weintraub, deep brain stimulation (DBS) is very helpful for motor symptoms, but not cognition.  In fact, it is possible that it worsens cognition, as people who have pre-existing cognitive impairment prior to surgery are at an increased risk of cognitive decline afterwards.  Dr. Bentley’s research focuses on response inhibition, which is a type of cognition that involves the ability to stop actions that are ongoing, and change response in the face of conflict.  She has studied what happens to prefrontal activity during a cognitive task, and if there is a type of stimulation different than that for motor symptoms that may be helpful for cognitively impaired individuals.  The first people who have received the treatment did show an improvement in their response and behavior during the stimulation, however the research is in the early stages. 

According to Dr. Shahnawaz, a blood test may be a key tool because there is no lab test.  A blood-based test is non-invasive compared to cerebral spinal fluid, inexpensive, and can be incorporated and used as a routine test.  Lewy bodies can be detected in biological fluids such as cerebral spinal fluid, blood, saliva and urine.  However, the quantity of oligomers is too low in biological fluids. Because of that, oligomers cannot be detected easily.  Dr. Shahnawaz is researching protein misfolding cyclic amplification (PMCA), which is used to increase the number of alpha-synuclein fibers in blood.  

Dr. Standaert discussed how the best test currently is the opinion of the movement disorder specialist. Unfortunately, this is only possible when symptoms are established which is too late for disease modifying therapies.

According to Dr. McFarthing, research gives people with PD hope for symptomatic treatments for today and hope for therapies that will slow or prevent the progression of the disease.  Research increases the chance of finding new therapies, and improving old ones to relieve symptoms and new ways of managing the day to day. Clinical research can also provide new ways to conduct preclinical and clinical studies. 

For a recording of this webinar, please see this APDA YouTube webpage.

See my notes below of the February 14th webinar. 

Regards, 

Joëlle Kuehn

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“Taking research from the lab to our lives” – Webinar Notes   

Speakers: 

• Nicole Bentley, MD, neurosurgeon, assistant professor of neurosurgery, University of Alabama, Birmingham, Alabama
• Kevin McFarthing, PhD, biochemist, diagnosed with Parkinson’s in 2012 at age 55
• Mohammad Shahnawaz, PhD, University of Texas Health Science Center, Houston, Texas
• David Standaert, MD, PhD, movement disorder specialist, University of Alabama, Birmingham, Alabama
• Daniel Weintraub, MD, psychiatrist, University of Pennsylvania, Philadelphia, Pennsylvania

Webinar Host:  American Parkinson Disease Association

Webinar Date:  February 14, 2021

Summary by:  Joëlle Kuehn, Stanford Parkinson’s Community Outreach 

Session 1: Investigating cognitive control and patterned DBS in PD with Dr. Bentley

Cognitive dysfunction in PD:

• Prevalent and disabling:
  • 25-30%  have mild cognitive impairment, up to 80% develop dementia after 15-20 years
  • Cognitive deficits outpace what is seen in the general population
• Affects many types of cognitive functions:
  • Memory, attention, processing speed
• Few treatment options:
  • Medications marginally helpful, deep brain stimulation has no effect or can worsen

Deep brain stimulation (DBS):

• DBS is very helpful for motor symptoms, but not cognition
• Implant device with a wire that goes into the brain to target structures deep inside
• By delivering electrical stimulation it can improve motor symptoms
• In order to study and understand cognitive function, we have to look at the frontal lobes primarily
• Response inhibition:
  • Type of cognition that involves the ability to stop actions that are ongoing 
  • Stopping prepotent actions
  • Changing response in face of conflict
  • Ex. about to start to cross a street, and saw a car coming, the ability to stop the action of walking is called response inhibition
  • Studies have shown that patients with PD have a lot of difficulty with this 

Dr. Bentley’s two research aims:

• What happens to prefrontal activity during a cognitive task?
  • If we can measure changes in activity, may be able to use that information to develop treatment
  •  How researched/tested this:
    • During surgical cases, place deep brain stimulator electrode as normal, and place a separate electrode that records brain activity, place in frontal area
    • It is temporary, it comes out in the end
    • Gives the ability to record from two different areas during a task 
    • Task example: press a button if you see on slides any letter other than X
      • Task is designed so you have the urge to press the button   
      • That tests response inhibition 
    • Results:      
      • Saw brain activity during theta-range when they are withholding the response
      • Increased theta power during withholding response
      • Muscle activity doesn’t have the same peak as when the correct letter (letter other than X) is on the screen so they are twitching but not moving
      • Trying to decide but at the same time see stark increase in same theta region of activity
      • Statistically significant increase in theta power 
      • Suggests that activity in this range of function may have something to do with the ability to withhold a response
• Can we deliver a different type of stimulation that is helpful for cognitively impaired individuals?:
  • Different patterns of DBS may affect different functions      
  • Question: Can different patterns be helpful
  • Trialing intermittent theta burst stimulation
  • Early stages
  • Unlike typical stimulation used for PD, theta burst stimulation deliver bursts of electrical stimulation at the same frequency
  • Results:
    • First people tried this on did show an improvement in their response and behavior during that stimulation   
• There is more to do in future research:
  • Additional data analysis with:
    • Enroll more participants
    • Distinction of cognitive impairment vs. no impairment
    • 2 targets of stimulation
  • Chronic stimulation

Session 2: Can we expect DBS to be used in the future to help cognition for PD? with Dr. Weintraub

DBS has wide brain effects and persistent effects on particular brain chemicals in cells that are associated with cognition and including the growth of nervous tissue in the brain

• Different stimulation therapies are used and being tested for cognitive impairment in various neurodegenerative diseases (Alyheimers, PD)
• Commonly used one today is external direct transcranial current stimulation (DCTS): 
  • Which is an electrical stimulation to the frontal part of the brain outside of the brain 
  • Sometimes paired with cognitive training where patient is participating in cognitive task at same time
• External intermittent theta burst stimulation:
  • Modification of commonly used procedure in psychology called repetitive transcranial magnetic stimulation (RTMS)
  • This also is to the front part of the brain and has shown preliminary benefit in Alzheimer’s and PD cognitive research
  • Main differences of intermittent theta burst stimulation and RTMS is it has a different wavelength and shorter total duration of treatment exposure required

Big picture DBS & cognition in PD:

• Literature says procedures are associated with slightly worse cognitive outcomes when used clinically for the treatment of motor symptoms
• But if you look at cognitive performance 6-12 months later, you may see a slight decline on average in patients that undergo DBS surgery
• However, when patients are younger and have better cognitive performance at baseline, the impact of DBS on cognition seems to be more neutral overall
• Recent research showed that it may be possible to change the stimulation site within the subthalamic nuclease for instance where electrical stimulation is placed to decrease cognitive delicene after surgery
• Also possible that lower frequencies overall may be associated with better outcomes  

Moving forward questions:

• Want to know if there are other cognitive abilities besides those linked with the front of the brain that might be targeted, i.e. memory with this kind of procedure?
• Beyond changing frequency of stimulation, what about changing the location within the subthalamic nucleus or the globus pallidus interna (those are the 2 major locations of DBS)?
• What is the potential impact of very low and altered frequencies on motor function?
• Is this envisioned as an actual treatment for cognitive impairment in patients with PD that is a reason to get the surgery or is it more conceptualized at thai point to minimize cognitive decline that can occur in some patients after DBS

Summary: Area of stimulation therapies either external or internal to the brain as a treatment for cognitive impairment and neurodegenerative diseases is an excited area of research and one worth exploring further

Session 3: Development of blood-based diagnostic test for PD with Dr. Shanawaz

Why is a blood test important for PD:

• Main problem when looking at a disease modifying therapy for PD is that the lack of early diagnosis
• Usually it is too late by the time the disease is diagnosed
• There is currently no laboratory test
• A blood-based test is:
  • Non-invasive
  • Inexpensive
  • Can be used as a routine test

What can we detect to diagnose PD:

• See in brain of PD patient an accumulation of alpha-synuclein proteins in the neurons
• Also called Lewy bodies, and the small clumps of alpha-synuclein are small, soluble and toxic
• Over time these neurons die and disappear which results in the onset of clinical symptoms and motor dysfunction 
• Formation of alpha-synuclein clumps starts years or a decade before onset of clinical symptoms
• Can be detected in biological fluids: 
  • Cerebral spinal fluid, blood, saliva, urine 
  • However, quantity of oligomers are too low in biological fluids because of that, oligomers cannot be detected easily
  • Question is how we can detect the oligomers

How can we detect the oligomers:

• Protein misfolding cyclic (PMC) amplification used to detect oligomers in biological fluids   
• Main aim is to increase number of alpha synuclein fibers using protein cyclic amplification and detect fibers easily
• Is a cyclic process of 2 steps (protein clumps incubation and fragmentation) that repeat themselves
• After number of cycles, large clumps (fibrils) form which can be easily detected using fluorescent dye
• Positive signal obtained from PD patient, and no signal obtained from sample of a healthy person 

Note: cerebrospinal fluid test for PD is being offered by Amprion now. Blood-based diagnostic test for PD is under development.

Session 4: When will a blood test for PD be available with Dr. Standaert

Commentary on cerebral spinal fluid (CSF) test available and potential for blood test for PD:

• Alpha-synuclein discovered to be connected to PD about 23 years ago
• Now finally beginning to understand critical role it plays in PD, that oligomers form and the oligomers are bad actors and are part of the problem in PD
• Development of a test to test this or look for this in patients is a really important milestone in field
• PD is a whole body disease:
  • Always think of PD as disease of brain, but and it’s true that many of the symptoms that we deal with are related to problems in the brain
  • But here were testing the blood and finding that there are abnormal proteins in the blood
• Emphasizes that PD is a whole body condition and not just a brain disease
• Why would you want to test for PD, can’t we already tell who has PD and who doesn’t?
  • Best test we have now is opinion of movement disorder expert, are pretty good when people have had PD for a number of years and symptoms are established, but not so great early on
  • Many patients have had trouble getting a diagnosis when symptoms are early and mild
  • PD could be confused with similar conditions, particularly early on          
• Real need is to think about how early can we go:
  • Can we actually detect these changes going on in someone before they have any symptoms of PD, any tremors, slowness, can you find these symptoms developing really early in the condition
  • Would be a tremendous advance because then we could talk not just about treating PD, but also preventing the appearance of physical symptoms of PD if we can detect it really early

Spinal fluid:

• Spinal fluid test is commercially available, some sites are using this
• Not all insurance companies will reimburse at this point, but it is a test that can be ordered, talk to your physician about it
• Don’t think the test is needed in most people who have well-established PD
• Far more useful in very early stages where there are questions about is this PD or something else, that is really the role of it

Blood tests are easier to get than spinal fluid, hopefully we can see that reach clinical use soon.

Note: there is also work going on on skin biopsies and testing that for the oligomers

Hopefully this will allow a more accurate diagnosis of PD:

• Movement disorders experts are in short supply
• Hopefully testing can reach people who maybe don’t have access to movement disorder specialist
• Hope this pushes timeline back and lets us detect the disease really early so we can take steps to prevent the appearance of the symptoms

Session 5:Role of PD research on lives of people with PD with Dr. McFarthing

What should the role of research be in the lives of people living with PD?

Developer of the Hope list:

• Wanted to find out what was happening in the areas of new therapy development
• Today list extends to 370 projects
• First thing research brings us, Hope
• Hope for symptomatic treatments for today and hope for therapeies that will slow or prevent the progression of the disease, stop it getting any worse
• If you don’t have access to the Parkinson’s hope list, it is open source (free to everyone), can google it

Research also brings knowledge:

• Research increases change of finding new therapies, improving old ones, and new ones to relieve symptoms and new ways of managing the day to day
• Research can also inform the discovery and choice of potential new therapies
• In terms of methodology as well, clinical research can provide new ways to conduct preclinical and clinical studies:
  • Clinical trials take a long time to complete
  • Take that time because safety and scientific integrity are very important

Biomarkers:

• Research can produce potential biomarkers that enable to monitor the progression and to conduct more efficient clinical trials
• We only know how we feel, we know how we feel can change from day to day, even hour to hour
• Scientists and clinicians can observe what we’re doing and come to their own conclusions, but they need to try and make their subjective observations into objective science
• To create / look for therapies that can alter symptoms and progression, we need good biomarkers

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Question & Answer:

Question:  What research is ongoing involving alpha-synuclein depletion and its impact on neurons and PD?

Answer (by Dr. Standaert):  There’s a lot of interest in the idea that if the problem is too much alpha synuclein, can we reduce the amount?  It’s not just a quantity of alpha synuclein, it is also the abnormal form of the oligomers.  We want to reduce not only the total amount, but also the abnormal synuclein. Companies are developing antibodies that can be infused once a month to decrease alpha synuclein, and are pretty late in the clinical trial.  Other approaches to reducing the expression of synuclein and approaches to enhancing the body’s normal mechanisms by which you clear the alpha-synuclein.  These have worked in animal models and are potentially viable.  The antibody approaches are well into phase 2 and 3 clinical trials and is an exciting area.  If you combine that with a blood test to identify somebody with abnormal synuclein early and then remove it, that is a potential prevention of PD.

Question:  Of all the trials you have collected, what is one of the most promising ones that you are excited about?

Answer (by Dr. McFarthing):  One that I find exciting is ANAVEX 2-73.  Results of a phase 2 trial of this drug were announced at the end of last year.  It’s a sigma 1 receptor activator which helps proteins to fold normally inside the cell.  In the phase 2 study, they found significant improvement in cognitive measures.  They also found a 14 point difference between placebo and ANAVEX 2-73 on the UPDRS, which is a PD symptom scale.  This is after 14 weeks of study.  There are a lot of cautionary notes because it is a phase 2 study, we need bigger numbers in phase 3, and the results have not been published in a peer review journal yet, but the top line looks very exciting.

Question:  Is the blood test for PD you were talking about now engaged in clinical trials, or is this still primary research?

Answer (by Dr. Shahnawaz):  Currently we are developing the blood test.  It is in research.  The main problem is the complexity of the blood matrix and the extremely low quantity of alpha-synuclein oligomers in the blood.  We are addressing these problems and are working on different approaches to concentrate alpha-synuclein oligomers from the blood, and to remove other contaminating proteins from the blood.

Question:  Focused ultrasound is another procedure currently available for PD motor symptoms.  Is there any thought for using focused ultrasound for cognition in the future?

Answer (by Dr. Bentley):  Maybe in the far future, but currently we know very little about cognitive networks.  Focused ultrasound creates an irreversible lesion, so we would have to know where to lesion exactly and how that particular area works with the rest of the network.  The neuromodulatory aspect is good, you can change the stimulation and other parameters, but there is still too much unknown to use that type of lesioning.

Question:  We discussed cognition and how other brain regions and other frequencies of stimulation may be investigated for cognition in PD.  Can you envision other symptoms of PD that DBS may be able to help if we choose the right frequencies or brain targets?

Answer (by Dr. Weintraub):  Within PD, there is similar research to what Dr. Bentley was describing, but focused on psychiatric symptoms, and have demonstrated that the stimulation parameters, whether location or frequency, post-surgery, may have differential impacts on depression and anxiety.  The people who do DBS will have more tools available to them to make adjustments.  Outside of PD, DBS is used for some psychiatric conditions either experimentally, or even clinically for OCD or major depressive disorder in the general population.  They use different areas than are used in PD.  DBS can also be used for substance use or addiction. There are a lot of psychiatric disorders that occur within PD as well, so it is possible that it will help for PD to some extent. 

Question:  Is it helpful to researchers to have PD listed on the death certificate? Are death certificates something researchers can use in their work?

Answer (by Dr. Standaert):  I think accuracy on death certificates is really important.  We actually don’t have really good data on how many PD cases there are in the US, or how many people die from it every year.  We have some rough ideas and a few states have registries, but for the most part the data is spotty.  We know PD is becoming more common because our population is aging, but we’re interested if there are other factors like environmental factors.  Death certificates are available to researchers and may be a key tool in understanding PD and what may be causing changes in numbers in the population.

Question:  Are there elements of the research pipeline that you find most frustrating?

Answer (by Dr. McFarthing):  The general problem and frustration in clinical trials is the time it takes.  It’s reasonable to understand why it takes a long time.  A factor could be the pace of recruitment, it takes a long time to recruit people for clinical trials, and a long time to get them through the treatment.  A characteristic of the progression of the disease with PD is that it is slow, which is good news.  However, this means that it takes a long period of time to get a reasonable statistically significant gap between the therapy and placebo groups.  Despite massive amounts of time and money in disease modifying therapies, we still don’t have any, and the only thing that has been shown to influence the rate of progression is exercise. 

Question:  In DBS, can multiple leads be placed in different parts of the brain at the same time and used for multiple issues: i.e. PD’s motor symptoms and cognitive issues?

Answer (by Dr. Bentley):  The short answer is yes.  Sometimes we do this currently in PD for severe refractory tremor where there are two targets that we can choose.  It is also used in other diseases to modulate more of the psychiatric indications that we’ve touched on.  For this particular cognition plus motor symptoms, it is an option that we can think about.  There are ways to cycle the stimulation.  We don’t want to lose the motor benefits that patients are getting, so we are thinking about things like administering theta burst stimulation during sleep when the motor symptoms aren’t as severe.  There are lots of creative ways where this can be used for a more personalized therapy.

Question:  When this blood test becomes available for PD, what quantity of blood would you envision would be needed to perform this test?

Answer (by Dr. Shahnawaz):  We can’t be sure when the blood tests will be available.  The problem is that the quantity of oligomers is very low compared to cerebral spinal fluid, where it can be detected very easily.  The complexity of the blood matrix, and contaminated proteins are also an issue.  We are currently working to increase the sensitivity of the PMCA, and are working to have our goal be 500 microliters of blood test for plasma, but we are currently at 1-2ml.  Our main goal is to increase sensitivity. 

Question:  Why is memory so important through DBS surgery?

Answer (by Dr. Weintraub):  There are a couple of reasons.  One is we do recognize that some patients, fortunately it is only a small minority of patients, can experience some meaningful cognitive decline post DBS, so we want to identify those people in advance to recommend that they not get surgery.  It seems that the people who have pre-existing cognitive impairment prior to surgery is a group that’s at an increased risk of cognitive decline afterwards, so that’s why you need to do detailed testing with a neuropsychologist for 1-2 hours to make sure it’s safe.