In early July, PMD Alliance presented a talk by Dr. Anthony Lang titled “New Frontiers in Neuroprotection.” His analysis explores the many ways researchers are attempting to slow or modify the progression of Parkinson’s and, more importantly, how promising each one seems to him.  We at Stanford Parkinson’s Community Outreach listened to the webinar and are sharing our notes. 

Dr. Anhony Lang is the founder of the Movement Disorders Centre at the University of Toronto. His work has inspired a generation of movement disorder physicians and researchers.

You can find a recording of the talk here.

If you have any questions about the presentation, contact PMD Alliance. 

For more information on the pharmacological treatments currently available for Parkinson’s, see the Stanford website.

Our notes are below.

Deven Shah
Volunteer

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New Frontiers in Neuroprotection – Webinar Notes

Presented by the Parkinson and Movement Disorder (PMD) Alliance July 10, 2020

Summary by Deven Shah, Stanford Parkinson’s Community Outreach

This presentation deals with the following question: can a single drug be appropriate in trying to slow the progression of Parkinson’s or not?

• This idea is called neuroprotection/disease modification, which describes treatment that can change the course of the disease.
• The answer is no. One drug cannot do so for everybody.

This field of disease modification is extremely active, with many different drugs that target many different biological processes being developed currently. For example, a drug in clinical trials tries to inhibit α-synuclein aggregations, while another uses gene therapy to fix GBA1, a gene responsible for sporadic Parkinson’s.

All of these clinical trials try to answer the question: can this specific drug be part of the effort to modify the disease progression of Parkinson’s? There are three different potential roles it can play, assuming the clinical trial succeeds.

1. It could be always used as the new single drug for everyone with Parkinson’s (not likely).
2. It could be always used in conjunction with existing drugs specific to people’s biological subtypes (more likely).
3. It could be occasionally used in conjunction with multiple other powerful drugs depending on which pathways doctors want to target (most likely).

Parkinson’s is a heterogeneous disorder.

• Clinically, this means that patients often present with different symptoms and progress at different rates.
• Pathologically, this means that some patients have Lewy bodies and others have pathologies that more closely resemble other dementias.
• Genetically, this means that there are lots of different genetic risk factors that most often conglomerate to elicit the Parkinson’s phenotype.
• Environmentally, this means that there are a multitude of substances that are known to sometimes cause Parkinson’s, and these substances vary based on a person’s genes.
• Most importantly, pathogenic mechanisms and cellular pathways differ from person to person. For example, some lose the ability to make enough energy for their neurons in a process called mitochondrial dysfunction, while others experience programmed neuronal death – also known as apoptosis. These mechanisms may occur independently or together to cause cell death. However, it is known that α-synuclein abnormalities are capable of inducing every one of these factors that lead to cell death.

So is Parkinson’s still a single disease? Or is it multiple?

• Argument for it being a single disease: things like genetic makeup, comorbidities, age of onset, strain of α-synuclein protein impact how Parkinson’s manifests itself from person to person, but it’s still fundamentally the same disease.
• Argument for it being multiple diseases: it presents so differently from group to group both pathologically and clinically that it cannot be accurately classified as the exact same disease.

There are three ways this idea of a multifaceted single disease / multiple diseases could implicate treatment:

1. It doesn’t. Even though the disease is multifaceted, all of its different subtypes still affect one common pathway, such as synuclein-related toxicity. If you target that pathway, it works for everyone.
2. It does slightly. There are many different cellular pathways, but one is sufficiently important where getting rid of it alters the progression of the disease. As a result, medicine that targets that important pathway, such as synuclein, doesn’t stop the disease entirely, but it still stops the majority of it.

3. It does significantly. There are many different cellular pathways that have different levels of importance depending on certain biomarkers, like whether you have a certain gene or have diabetes. As a result, certain people will need certain amounts of medicine.

Precision medicine is all about getting the right patient the right dose of the right drug at the right time (the 4 “rights”). Dr. Lang proposes that it should be “drugs” instead of “drug,” since multiple pathways could be at work in one patient. Other fields of human biology, such as the study of cancer or the study of Alzheimer’s, have already been using combinations of drugs to treat illnesses, so it would make sense to carry this over into Parkinson’s research.

So if it is true that using combinations of drugs is necessary to treat Parkinson’s, how can researchers work to develop and test these combinations?

The DATATOP trial – tested the efficacy of using deprenyl in conjunction with vitamin E to treat Parkinson’s (based on the corollary I-SPY trial, which tested the use of 3 treatments combined on breast cancer).

Multi-Arm Multi-Stage (MAMS) trials – where there are many experimental groups and only one common control group (multi-arm) and experimental treatments are discontinued/continued based on whether they show promise (multi-stage). This has been used in clinical trials of STAMPEDE’s effect on prostate cancer.

Basket trials – targeting shared pathogenic mechanisms in different subtypes of PD. Other justifications for using multiple drugs:

• There are so many distinct biological disorders / molecular phenotypes or so many contributing

biological mechanisms in a single disorder that no one drug can cover them all.

• Multiple drugs are still good even if the disease only involves a single pathway, as you can disrupt different parts of the pathway with multiple drugs.

Thus, we come full circle back to the initial question, which asks if we need to revise our outlook on Parkinson’s, or reconstruct it. It asks whether Parkinson diseases are similar enough where one drug can work or if they are so different that no drug can cover all of them. And the answer is somewhere in the middle.

Not all Parkinson’s Diseases are the same, and so if one drug is going to work, it is likely going to target shared pathogenic mechanisms of different subtypes of the disease. But because there are likely multiple shared pathogenic mechanisms, we will need multiple of these drugs.

Question and Answer Session

Q: How are patients supposed to understand all these complexities with the testing and manufacturing of drugs so that they can decide what is best for them?

A: Parkinson’s patients need to participate in trials. Without participation and understanding of the important contribution that you make the Parkinson’s community wouldn’t have the plethora of research it does today. Patients are even sometimes on advisory boards of trials, so you will be able to provide your input and help scientific research meet your needs and the needs of others.

Q: Do these different subtypes of Parkinson’s Disease include atypical Parkinson’s Disease? A: No, they do not.

Q: In rural and remote areas, how can we participate in clinical trials?

A: It’s tough. There are certain methods that allow participation virtually, which have increased in popularity during COVID, but experimental therapies often have to have in person monitoring and administration.

Q: Are there any lifestyle changes/integrated medicine therapies that can make a difference in the progression of Parkinson’s Disease?

A: The incidence of Alzheimer’s-related dementia is falling because comorbidities such as hypertension or diabetes are falling, so clearly certain things can make a difference in neurodegenerative diseases. In Parkinson’s, a balanced Mediterranean diet with vegetables/lean meat has been shown to have a positive impact. Exercise may not alter your brain to change the neuropathology of PD, but it definitely reduces cardiovascular comorbidities. It also means you are more active and so mentally tolerating the movement-related symptoms of Parkinson’s is easier.

Q: At this moment, what is the top new therapeutic that is the most exciting to you?

A: You have to classify therapeutics between dopamine and non-dopamine therapies. With dopamine, the best new medicines change the way we administer the neurotransmitter. Instead of administering levodopa orally, which has to travel through the digestive system, then the vascular system, then finally across the blood brain barrier, we need to find even-acting, quick methods of administering levodopa, such as infusing the drug. Other treatments that were game changing include DBS (Deep Brain Stimulation), but it sometimes caused more problems than it solved, such as worsening memory problems in more elderly Parkinson’s patients. Non-dopaminergic features such as thinking/memory problems, behavioral changes, autonomic nervous system dysfunction, or even motor symptoms that become increasingly resistant to levodopa such as postural instability can only be resolved by non-dopaminergic therapies, however. Therapies that resolve these things would be exciting.

Q: Do vitamins help?

A: Multivitamin supplements are advisable for all Parkinson’s patients. They increase bone health and help keep the immune system strong. However, there is no proven benefit in terms of Parkinson’s disease itself, so do not spend a fortune buying multivitamin supplements.

Q: Does sleep affect Parkinson’s Disease?

A: Good sleep has been shown to help clear abnormal proteins in the brain. As a result, a good night’s sleep may actually be doing some good for the underlying disease. Conversely, Parkinson’s affects sleep. It sometimes leads to REM behavior disorder, and medicines that treat Parkinson’s also occasionally affect sleep quality.

Q: Can you speak about the mind-body connection and the human spirit? It can be about advocacy, hope, or something else.

A: A good movement disorder specialist doesn’t just deal with movement disorders. You’re not just a tremor/walking problem. You are a human being – and that means you bring your emotional, physical, and social baggage to the ailment you are suffering from. It is often these experiences that shape the nonmotor aspects of Parkinson’s Disease. Parkinson’s isn’t just a movement disease – it’s an experience – and a good doctor understands that. The human spirit is never broken. Take the example of Jack Clark, who my position is named after, who suffered from Parkinson’s Disease. Even as his disability increased, he still dedicated all of his time attempting to persuade the rich and powerful to donate to his cause.