In a paper published today in the high-profile journal Lancet Neurology, a consortium of Canadian Parkinson’s researchers including Drs. Jon Stoessl (UBC), Anthony Lang (University of Toronto) and Ronald Postuma (McGill University), together with other renowned international authors from Germany and the United States, propose a biologically-based, three-part classification for Parkinson’s disease (PD) in line with today’s knowledge of the complex causes and variations of the disease. In order to make progress in developing therapies that can modify or cure PD, exact classification and stratification is essential to facilitate meaningful study results.
Parkinson’s disease is a common chronic, progressive neurodegenerative disease with a continuously increasing incidence and prevalence worldwide – there are currently more than 100,000 people affected in Canada, with more than 10,000 people newly diagnosed each year. There is currently no cure for the disease, but relatively good symptomatic treatment is now possible, including medication and surgical approaches, but so far, there is no therapy shown to modify disease progression. Diagnosis is based primarily on typical clinical features of slowness of movement, stiffness and tremor. The classification of different forms of Parkinson’s disease is also based primarily on clinical criteria, in some cases supported by diagnostic imaging (e.g. MRI). A special feature of Parkinson’s disease is the so-called prodomal phase, where early symptoms can occur decades before the later diagnosis that is based on characteristic motor features. In the prodomal phase and the early stages of disease, PD and related disorders are often difficult to distinguish from each other.
Parkinson’s disease is one of the so-called synucleinopathies, which are neurodegenerative disorders where deposits of the protein α-synuclein accumulate in certain brain regions. In the case of PD, these aggregates are the result of proteins misfolding and are histologically detectable in tissue as so-called Lewy bodies (in cell bodies) or Lewy neurites (in nerve terminals). Dopamine-producing neurons are particularly affected and their decline causes dopamine deficiency, which leads to Parkinson’s symptoms. While various pathogenic gene variants are known, they directly cause only a small number of cases and there are also genetic factors (risk variants) that lead to an increased susceptibility to disease. In the case of sporadic and genetic forms of Parkinson’s disease, the basic underlying mechanisms are generally similar, but forms of Parkinson’s without Lewy bodies are now also recognized.
For years, research has been making steady progress in understanding the underlying causes of Parkinson’s disease and their complex interplay, and it is hoped that therapies targeting these causes will be available in the next ten years.
“Advances in the development of sensitive and specific in vivo biomarkers for the presence of α-synuclein pathology have brought Parkinson’s research to a critical point where a shift from largely clinically based diagnostic criteria to an emphasis on the biological basis of the disease is necessary,” says Dr. Stoessl, Professor of Neurology in the Faculty of Medicine at UBC.
The new “SynNeurGe” system is intended to make it possible to define, identify and address the molecular basis of PD before the onset of characteristic motor features. It comprises three main components:
- the “Parkinson’s-type synucleinopathy” (i.e. the presence or absence of pathological α-synuclein (‘Syn’) in tissues or cerebrospinal fluid)
- evidence of Parkinson’s-associated neurodegeneration (‘Neur’), currently mainly defined by specific neuroimaging techniques
- the detection of Parkinson’s-specific pathogenic gene (‘Ge‘) variants that cause PD or strongly predispose to it
This biological ‘SynNeurGe’ classification is associated with a clinical syndrome. The transition from a purely clinically 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 needed to develop clinically meaningful disease-modifying therapies. This classification system will serve as the basis for future biomarker-based subgrouping and staging systems that enable the implementation of precision medicine approaches to disease modification. Only if an exact definition or stratification of the investigated cohorts is possible can new drugs that target different molecular mechanisms be accurately investigated for their efficacy.
“There are significant ethical implications for early diagnosis of disease and as new biomarkers are developed and refined, the specific criteria may require modification over time. We therefore emphasize that these criteria are currently proposed exclusively for research,” says Dr. Stoessl. “The current research proposal is the first step in a crucial process to move Parkinson’s research from a purely clinical definition to a biologically oriented approach that will hopefully facilitate the development of precision-based disease-modifying therapies.”