Pinpointing the earliest stages of Parkinson’s: A Q&A with Dr. Daniela Berg

Each year during our Grand Challenges in Parkinson’s Disease symposium, Van Andel Institute presents the Jay Van Andel Award for Outstanding Contributions to Parkinson’s Disease Research to a scientist or scientists whose work is transforming our understanding of Parkinson’s. This year, we’re pleased to honor Daniela Berg, M.D., and Ron Postuma, M.D., M.Sc., for their groundbreaking efforts to identify the earliest symptoms of Parkinson’s disease and to translate their findings into new diagnostic criteria. Dr. Berg is the chair and director of the Department of Neurology at Christian-Albrechts-University in Kiel, Germany. Dr. Postuma is a professor of neurology at McGill University in Montreal, Canada.

VAI Voice caught up with Dr. Berg to discuss what we know (and what we don’t) about the earliest stages of Parkinson’s and how this knowledge could inform future ways to diagnose and treat the disease. 

Photo courtesy of Dr. Daniela Berg

Q: How has our understanding of Parkinson’s changed in the last decade, especially as it relates to the earliest stages of the disease?

DB: In fact, it changed dramatically with observations that came even earlier than a decade ago. The first completely unexpected finding was that the pathological process known to lead to the degeneration of dopaminergic neurons does not start in the substantia nigra but at quite distant parts of the nervous systems, such as in nerve cells of the olfactory bulb or gut.

In parallel, the second so far neglected observation was that Parkinson’s disease patients frequently report non-motor symptoms occurring years to decades before the typical motor symptoms allow diagnosis. This phase preceding the clinical phase is called prodromal phase of Parkinson’s disease (PD). We thus understand Parkinson’s disease now as a disorder encompassing the entire nervous system leading to other than the typical motor symptoms long before clinical diagnosis can be made.

Q: How does an improved understanding of prodromal Parkinson’s impact development of potential diagnostic methods/criteria and therapies? Could it possibly inform preventative measures in the future?

DB: One of the major challenges in treating Parkinson’s disease is that more than half of the dopaminergic neurons have already degenerated when motor symptoms manifest that allow clinical diagnosis. This on the one hand shows the great capacity of our brain to compensate for huge deficits. On the other hand, any disease-preventing or, at least, disease-modifying therapy comes too late at this stage.

For truly effective disease-modifying therapies, earlier diagnosis is essential, which is only possible when there are so-called “markers” — such as clinical symptoms, biomarkers derived from blood, spinal fluid or other biomaterial or imaging — that allow the identification of individuals in the very early phase of neurodegeneration, also called the prodromal phase. A better understanding of this phase may foster the development of new markers.

As an example: We know that individuals with hyposmia, or loss of sense of smell, have a slightly higher likelihood of being in the prodromal phase than individuals with normal olfactory function. However, this symptom is fairly unspecific and the increase of likelihood of being in the prodromal phase is rather low. However, if this individual has a family history of PD along with constipation and depression then the likelihood of being in the prodromal phase increases.

The possibility of adding different prodromal markers to calculate the risk of being in the prodromal phase is used in a statistical model that is the basis of the current research criteria for prodromal PD. In individuals with a high risk of being in the prodromal phase, additional biomarkers for PD may be identified that strengthen the diagnosis. In the future, once diagnosis of prodromal PD becomes highly likely, preventive therapies may be deployed.

It is important to know that several other challenges also need to be met before therapies are started in this phase, such as identification of progression markers that may serve as endpoints for clinical studies.  

Q: What is the most important thing for people reading this to know about the earliest stages of Parkinson’s?

DB: There are many different markers that may occur in the early, prodromal stage of Parkinson’s. Most of them are fairly unspecific, which means that they are quite prevalent and only rarely a prodromal sign of PD (at least when they occur on their own). Examples include hyposmia, or reduction to loss of sense of smell; depression; urinary dysfunction; and constipation.

However, one symptom called REM Sleep Behaviour Disorder (RBD) is, at least in individuals older than 50 years, very frequently associated with the later development of clinical PD or similar disorders with alpha-synuclein pathology. Individuals who realize (or whose bedpartners realize) that they act out their dreams with strong movements should see a specialist to treat the sometimes dangerous symptoms of RBD and to explore diagnosis of Parkinson’s as early as possible. If diagnosed, this may in the future enable participation in a clinical study for preventive therapies.

It also is very important to know that the prodromal phase may last years to decades. The best preventive therapy we know about so far is physical activity. Thus, an increased likelihood of being in the prodromal phase of PD should lead to an active lifestyle that includes an increase in physical activity.

Also, mental activity is good for the brain (not only in the preventive concept of PD but also of dementia) and several nutritional elements may be considered: caffeine, nutrients with high levels of polyphenols and vitamins (i.e., “healthy food”). Thus a “healthy lifestyle” regarding physical and mental activity as well as nutrition can be beneficial in the prodromal phase – not only for modulation of the underlying neurodegenerative process but also for prevention of other neurological (e.g., dementia) or cardiovascular diseases.

Q: What are some of the critical gaps in knowledge when it comes to prodromal Parkinson’s?

DB: Currently, we do not know who with a specific combination of prodromal markers will develop clinical PD and if so when (exceptions are some genetic forms and RBD as a symptom).

It will be essential to identify biomarkers which confirm the neurodegenerative process in the prodromal phase as well as progression markers in the prodromal phase, which may serve as endpoints for clinical studies. Without these progression markers, any clinical study would need to be designed to last for many years as, so far, only conversion to clinical manifested Parkinson’s or a clearly progressing dopaminergic cell loss on nuclear imaging techniques may serve as endpoints.

Q: Where do you see Parkinson’s research going in the next five years?

DB: There are several important research avenues that need to be followed:

  • A better understanding of pathology — that is, what initiates the pathological process?
  • Identification of highly sensitive and specific biomarkers for diagnosis and progression in the prodromal and clinical phase.
  • Development of individualized therapies tailored to individual genetic and phenotypic profiles.
  • Comprehensive, multi-professional care concepts in all stages of the disease. 

Q: What is the most exciting thing going on right now in your field? What gives you the most hope?

DB: There are several exciting things going on:

  • Several studies for disease-modifying therapies in the early stages of PD that may be moved into the prodromal stages if successful.
  • Exciting biomarker research for early detection and progression monitoring.
  • There are new therapeutic strategies also for late stages of the disease like MRgFUS (MR-guided focused ultrasound).

Grand Challenges in Parkinson’s Disease and Rallying to the Challenge are going virtual for 2020! Learn more at grandchallengesinpd.org.