14 February 2017 – A group of German neurologists have managed to detect Parkinson's disease for the first time using a small skin sample – years before the emergence of the typical motor signs such as slow movement (akinesia), shaking (tremor) at rest or feeling of muscle stiffness. According to a joined press release by The German Society of Neurology (Deutsche Gesellschaft für Neurologie, DGN) and the German Parkinson Society (Deutsche Parkinson Gesellschaft, DPG), the diagnosis was made possible through the histological detection of pathological protein deposits in the skin's fine nerve endings. The scientific article, which has now been published in the highly respected journal "Acta Neuropathologica", denotes a milestone in Parkinson's diagnostics and paves the way to develop new therapies for the difficult-to-treat neurodegenerative disease.
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Press release in German language
Parkinson's disease is one of the most common disorders affecting the central nervous system. It is estimated that 220,000 people suffer from Parkinson's in Germany, making it the second most common neurodegenerative disease after Alzheimer's dementia. Parkinson's disease is particularly difficult to diagnose at an early, i.e. prodromal stage as it first emerges as nonspecific complaints such as an impaired sense of smell, depression or digestive disorders. Only when the typical motor symptoms set in – slow movement (akinesia), shaking (tremor) at rest or feeling of muscle stiffness – can a doctor diagnose a patient with Parkinson's disease. By the time this stage is reached, however, neuronal cells have been dying off for years; around 80 per cent of dopaminergic nerve endings and up to 50 per cent of neuronal cells in the brain's substantia nigra have already been irreversibly lost. The development of effective therapies is obstructed by the fact that Parkinson's patients are not identified as such until this late stage of the disease. If physicians were able to intervene at an earlier stage, the prospect of developing treatments, and also of treatment success, would be much higher.
Known central biomarker; now identified in the periphery before the presence of clinical Parkinson symptoms
All around the world, numerous research groups are working on ways to detect Parkinson's disease at an earlier stage. The collaboration of the teams of neuroscientists and neurologists with Dr Kathrin Doppler and Professor Claudia Sommer from Würzburg as well as with Professor Wolfgang Oertel from Marburg has now published a groundbreaking scientific contribution. They were able to identify the alpha-synuclein biomarker, an indicator of Parkinson's disease, in the skin of high-risk patients suffering from REM sleep behaviour disorder years before the patient developed visible motor symptoms. "This means we are a huge step closer to our primary goal of identifying and stopping Parkinson's at an early stage," comments Professor Günther Deuschl, Parkinson's expert at Schleswig-Holstein University Hospital in Kiel and President of the European Academy of Neurology. "The path has now been opened to identify a diagnostic marker in the early phase of the disease, also for patients who do not suffer from REM sleep behaviour disorder. With this, we are finally within reach of a long awaited presymptomatic Parkinson's therapy."
"With their paper, Dr Doppler and colleagues have made a highly significant contribution to the current landscape of international Parkinson research," remarks Professor Werner Poewe, Director of the Department of Neurology at the University Medical Centre in Innsbruck, Austria. "Important here is the potential of an easily applicable skin biopsy method that is minimally invasive and requires a sample measuring just five millimetres. This is of direct and practical significance in terms of identifying patients to take part in trials on Parkinson's prevention."
Professor Wolfgang Oertel has performed this scientific work as part of his Hertie-Senior-Research Professorship "Clinical Neuroscience", which he holds since 2014. The Hertie-Senior-Research Professorship is awarded by the Charitable Hertie-Foundation, Frankfurt/Main, Germany, the largest private foundation for the support of brain research in Germany.
Detection previously only possible in the brain
"We are already familiar with alpha-synuclein as a neuropathological indicator of Parkinson's disease, and the identification of these protein deposits was already seen as the gold standard of diagnosis," explains Professor Jens Volkmann, Chairman of the Department of Neurology at the University Hospital of Würzburg and co-author of the study. "However we were looking at the brain, which was only possible post mortem," says the president of the German Parkinson Society. The Würzburg researchers were already able to demonstrate that alpha-synuclein is not only deposited in the brain but also in the skin back in 2014. They found pathological protein aggregates in the skin's small nerve fibres in approximately half of the examined Parkinson's patients.
In their current study, the two collaborating teams went one step further: in order to find out whether alpha-synuclein can also be used as a biomarker during the prodromal phase, the group examined patients with REM sleep behaviour disorder (RBD). The dream- sleep disorder is classified as an early prodromal symptom typical of Parkinson's disease. It manifests itself in aggressive dreams and violent movements when dreaming; around 85 per cent of those affected with RBD go on to develop Parkinson's within the 15 to 20 years that follow. Alpha-synuclein deposits are also found in the brains of people suffering from REM sleep behaviour disorder.
Promising path to developing drugs against Parkinson's disease
"Our study offers evidence to show that phosphorylated alpha-synuclein is already existent in the dermal nerve fibres of patients suffering from REM sleep behaviour disorder. With these patients, the deposits can be viewed as peripheral histopathological markers of an alpha-synucleinopathy which emerges before the onset of motor symptoms associated with Parkinson's disease," writes lead author Dr Doppler. Considering the ease of access to skin biopsies and the high specificity of the examination, the authors see great potential in the method in terms of identifying Parkinson's patients in the prodromal stage of the disease and being able to enrol these patients in clinical trials to investigate disease-modifying drugs.
Between December 2014 and July 2016, the researchers recruited 18 patients with REM sleep behaviour disorder, 25 patients with early Parkinson's disease and 20 healthy control subjects from the neurology departments of Würzburg and Marburg university hospitals to take part in the trial sponsored by ParkinsonsFonds Deutschland. They took skin biopsies (5mm) from the test subjects' backs in the areas C7 and TH10 as well as from the upper and lower legs and assessed them for phosphorylated alpha-synuclein deposits in the dermal nerve fibres using double-immunofluorescence labelling. A nuclear medicine examination (FP-CIT-SPECT) was also performed to determine the density of presynaptic dopamine transporters in the basal ganglia; olfactory function tests were carried out and likelihood ratios for prodromal Parkinson's symptoms calculated.
Phosphorylated alpha-synuclein was visualised with a sensitivity of 55.6 per cent in 10 out of 18 RBD patients. Out of 25 patients with Parkinson's disease 20 subjects were found positive for the alpha-synuclein deposits in skin resulting in a sensitivity of 80 per cent for manifest PD. As no deposits were identified in the skin biopsies of healthy control subjects, the applied method has a specificity of 100 %.
Joint press briefing published by the German Society of Neurology and the German Parkinson Society
Doppler K et al. Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease. Acta Neuropathologica 2017; DOI: 10.1007/s00401-017-1684-z
Doppler K et al.: Cutaneous neuropathy in Parkinson’s disease: a window into brain pathology. Acta Neuropathologica; 2014; 128(1): 99–109, DOI: 10.1007/s00401-014-1284-0
DGN press release dated 21 September 2016: Guter Schlaf schützt das Gehirn – schlechter Schlaf fördert Alzheimer und Parkinson (mit Video)
Specialist contact in case of queries
Professor Wolfgang H. Oertel
Hertie Senior Research Professor and Professor for Neurology
Philipps-Universität Marburg, Neurology Clinic
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As a specialist society for neurology, the German Society of Neurology (Deutsche Gesellschaft für Neurologie e.V., DGN) views itself as bearing a social responsibility for safeguarding neurological patient care in Germany for its over 8,000 members. The DGN therefore supports science and research as well as teaching and further training in the field of neurology. It is an active participant in discussions on health policy. The DGN was founded in Dresden in 1907 and is now based in Berlin.
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Past President: Professor Ralf Gold
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