New biological classification of Parkinson's disease

(umg) Parkinson's disease is a chronic disease that occurs frequently worldwide and is associated with the loss of nerve cells. According to the German Center for Neurodegenerative Diseases (DZNE), there are currently at least 200,000 people affected in Germany. The disease is not yet curable, but relatively good symptomatic treatment from medication to brain pacemakers is now possible, although the cause of the disease cannot be treated. Diagnosis is based on clinical features such as the presence of typical motor symptoms, for example tremors in the hands, arms, feet and/or legs or slowness, lack of movement and immobility. The diagnosis is supplemented by imaging procedures such as magnetic resonance imaging (MRI) of the brain. The classification of different forms of Parkinson's is also primarily based on clinical criteria. A special feature of Parkinson's disease is the so-called prodromal phase, in which early symptoms (prodromes) can occur decades before the diagnosis is made. In this phase and in the early stages, Parkinson's disease and related neurodegenerative diseases ("synucleinopathies") are often difficult to distinguish from one another.

Synucleinopathies are pathological deposits of the protein α-synuclein in certain regions of the brain. These accumulations of α-synuclein in the nerve cells are caused by a faulty molecular protein structure (spatial misfolding), which initially results in the formation of tiny protein fibers that then clump together and have a cell-damaging effect. These accumulations are usually detectable as so-called Lewy bodies in the tissue. Dopamine-producing nerve cells are particularly affected, and the Parkinson's symptoms are caused by their destruction or the resulting lack of dopamine. Various changes in the genetic material, so-called mutations, are known. However, these "Parkinson's genes" only directly cause a small number of cases of the disease. There are also genetic factors that increase the likelihood of developing Parkinson's disease. The basic disease mechanisms are the same for sporadic and genetic forms of Parkinson's disease. However, forms of Parkinson's without Lewy bodies are now also known.

For years, research has been making ever greater progress in clarifying the mechanisms of Parkinson's disease and their complex interplay, so that it is hoped that in the next ten years it will be possible to use therapies that target the molecular causes.

With their new S-N-G classification, the researchers, alongside Prof. Dr. Tiago Outeiro, Prof. Dr. Günter Höglinger (Munich), Prof. Dr. Daniela Berg (Kiel) and Prof. Dr. Christine Klein (Lübeck) as well as renowned international colleagues, are proposing a new system for Parkinson's disease to enable earlier diagnosis and more targeted treatment. The "S-N-G" system is intended to help define and identify the molecular basis of Parkinson's disease even before symptoms appear and to target it therapeutically. It comprises three main components: 1) "Parkinson's-type synucleinopathy," which is the presence or absence of abnormal α-synuclein (S) in tissues or cerebrospinal fluid; 2) evidence of Parkinson's-associated neurodegeneration (N), the loss of neurons and cell function defined by specific neuroimaging techniques; and 3) the detection of Parkinson's-specific disease-causing gene variants (G) that trigger or strongly favor Parkinson's disease. This biological "S-N-G" classification is associated with a clinical syndrome ('C') defined by one highly specific trait or several less specific traits.  "Our research focus at the UMG has been particularly on the classification of 'Parkinson's-type synucleinopathy'. It is time to rethink outdated treatment concepts and adapt treatment measures to our current state of research and knowledge," says Prof. Dr. Outeiro, Director of the Department of Experimental Neurodegeneration at the University Medical Center Göttingen (UMG), and adds: "With our new classification, we want to move Parkinson's research from a clinical approach to a biological approach. If we can address the cause of the disease directly with the treatment, this would improve the prospects of a possible cure."

The results have been published in the renowned journal Lancet Neurology.

Original publication:
Höglinger GU, Adler CH, Berg D, Klein C, Outeiro TF, Poewe W, Postuma R, Stoessl AJ, Lang AE. SynNeurGe: Research criteria for a biological classification of Parkinson’s Disease. The Lancet Neurology 2024, Vol. 23, Issue 2, P191-204. DOI: 10.1016/S1474-4422(23)00404-0.

This transition from a purely clinical-based diagnosis to a biological classification is essential for the next phase of basic and clinical research studies and brings research closer to the precision medicine required for the development of clinically significant disease-modifying therapies, according to the team of authors. If future studies on the various forms of Parkinson's disease or synucleinopathies provide an exact definition of the patient groups being investigated, new drugs that target different molecular mechanisms can be reliably tested for their efficacy; for example, no therapeutic strategy that targets Lewy bodies should be tested on patients with Parkinson's disease without Lewy bodies.


CONTACT
University Medical Center Göttingen, Georg-August-University
Department of Experimental Neurodegeneration
Prof. Dr. Tiago Outeiro
Waldweg 33, 37073 Göttingen
Phone +49 551 / 39-67951
tiago.outeiro(at)med.uni-goettingen.de