I just wanted, as a synuclein researcher and a practicing clinical neurologist dealing with patients afflicted with synucleinopathies and other related conditions, to share my excitement about the recent developments in biomarkers centered around alpha-synuclein (also known as α-synuclein). It has been known for some time that abnormal conformations of α-synuclein play a central role in the pathogenesis of these disorders, but up till recently biomarker studies based on this protein had not provided a good separation of people with synucleinopathies from the control population. Recently, a number of studies have shown that application of two different methods in the human Cerebrospinal fluid can detect abnormal conformations of α-synuclein, and are able to separate people with synucleinopathies from controls and from patients with other neurodegenerative diseases with high specificity. This means that most, in fact almost all, patients with a clinical diagnosis of a synucleinopathy tested positive, whereas almost all other subjects tested negative. Both methods, termed “Protein Misfolding Cyclic Aplification” and “Real Time Quaking-Induced Conversion” had previously been used in the field of prion diseases, and are based on the idea that even a minute amount of abnormally folded α-synuclein in the cerebrospinal fluid can be amplified and detected. This follows the wealth of data suggesting that α-synuclein may behave in a prion-like fashion and transmit disease across brain regions. Although data are still scant, there is some suggestion that these methods can detect these abnormal α-synuclein conformations also in presymptomatic subjects, who have not yet developed the overt motor symptoms associated with PD diagnosis. Whether such methods can be used in a quantitative fashion to follow disease progression is not clear, and requires further work. In any case, in my mind these studies represent milestones in the understanding, detection, and potential treatment of patients with Parkinson’s disease and related conditions. They reinforce the central role of α-synuclein in the pathogenesis of the disease, and they may be helpful in sub-dividing patients in categories based on the presence or not of abnormal α-synuclein conformations. They appear to be very accurate in separating out patients with Parkinsonism who do not have a synucleinopathy, such as patients with Progressive Supranuclear palsy. They may help select patients for clinical trials in which α-synuclein is targeted.

These significant advances, that may have a practical impact on the clinical management of people with Parkinson’s Disease and related conditions, have only been made possible through the participation of people with such disorders in these studies. These patients, and controls, have donated cerebrospinal fluid following lumbar puncture, a somewhat invasive procedure, which, however, is largely harmless. This is the only way to gain access to the fluid circulating around the brain, which reflects ongoing brain processes. This serves to make the point of the importance of the participation of patients in biomarker studies and clinical trials; significant advances can only be made through their active involvement.

A press release, with little additional scientific data so far, has also indicated that there may be some potential in the development of a new radioactive tracer to detect abnormal conformations of α-synuclein in the brain of living subjects, through Positron Emission Tomography (PET). Clinical studies are set to begin later this year. If this or another tracer is successful in detecting such brain pathology, this will be a tremendous advance, as this can be followed in living subjects over time, in response to disease-modifying treatments. Together with the advances in the detection of abnormal conformations of α-synuclein in the cerebrospinal fluid, and the ongoing clinical trials targeting α-synuclein, the feeling is that a new “α-synuclein era” begins in the field of Parkinson’s disease research and management, with practical implications for patients and their families.
______________________________________________________________

Leonidas Stefanis, MD, PhD presented at the 4th World Parkinson Congress in Portland, Oregon. He is currently a Professor of Neurology and Neurobiology at the University of Athens Medical School and Director of the Laboratory of Neurodegenerative Diseases at the Biomedical Research Foundation of the Academy of Athens.

Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®