Admin_Adham
“Parkinson’s disease is the fastest-growing neurological disorder,” commented Daniela Berg, MD, president of the German Neurological Society (DGN), at a press conference held at the DGN Congress 2025.
In Germany, an estimated 300,000-400,000 people are living with the disease. Worldwide, about 11.8 million people were affected in 2021, and this number is estimated to reach 25.1 million by 2050. “We are almost dealing with a pandemic,” said Berg.
The congress discussed approaches to better understand the disease from its biological causes and what benefits this could have for prophylaxis, diagnosis, and therapy.
Lost Time Before Therapy
Jannik Prasuhn, MD, of University Hospital Schleswig-Holstein in Lubeck, Germany, and Johns Hopkins University in Baltimore, described the current situation as precarious. There are currently no disease-modifying therapies, and diagnosis relies on clinical criteria that cannot definitively identify the disease. A pathologically confirmed diagnosis is still only possible postmortem, he noted.
The clinical criteria capture only the consequences, not the causes of the disease, Prasuhn said. Heterogeneous disease courses, clinical overlaps, and differential diagnoses such as multiple system atrophy with parkinsonism or other synucleinopathies further complicate diagnosis.
Even in expert centers, there is only about an 80% agreement between clinical and neuropathologic diagnoses, the researcher pointed out. “The clinical definition simply falls short,” he stated. “And it is only of very limited use — if at all — for interventional studies.”
The pathology, such as the deposition of alpha-synuclein, remains invisible for decades until the first symptoms finally appear. However, the clinical phase only begins when 70%-80% of the dopamine-producing neurons have already been lost.
This represents a lost window of opportunity for disease-modifying therapies currently under development. Prasuhn therefore posed the question: “Can we also define Parkinson’s disease biologically and not just describe it at the onset of symptoms?”
Detecting Parkinson’s Disease Early
A biological definition of Parkinson’s disease depends on the ability to detect misfolded alpha-synuclein in cerebrospinal fluid (CSF) or blood. This is now possible with a seed amplification assay (SAA). This technique allows patients to be identified even in the prodromal phase of the disease, as well as asymptomatic carriers of the mutation.
SAA
Samples for SAA can be obtained from skin, blood, CSF, or tears, depending on the disease context. In Parkinson’s disease, CSF is used. Alpha-synuclein is then isolated from the sample. This serves as the “seed.”
According to the prion hypothesis, misfolded protein from samples taken from patients with the disease can induce other alpha-synuclein monomers to misfold. Over time, this leads to increasing aggregation of misfolded protein in vitro. Using thioflavin T, a dye that binds protein aggregates, this process can be visualized in real time as a fluorescence intensity-time curve.
Patients who test positive in the assay are considered to have a synucleinopathy, whereas those who test negative do not.
In Germany, the assay is currently used exclusively within the context of clinical trials.
Following the example of Alzheimer’s disease (amyloid, tau, and neurodegeneration system) or Huntington disease (Huntington Disease Integrated Staging System), a biological definition can now supplement or replace the clinical syndrome designation for Parkinson’s disease. The guiding principle of this paradigm shift, Prasuhn said, is simple: “Biology is the disease; the clinical presentation is only its manifestation.”
A biological classification would be based on three core markers:
- Synucleinopathy: Pathological alpha-synuclein detected by SAA
- Neurodegeneration: Dopaminergic dysfunction detected by DaT-SPECT/PET, FDG PET, or MIBG-SPECT
- Genetics: Pathogenic or risk variants in SNCA, GBA1, or LRRK2
On the basis of these markers, two classification systems have been proposed:
- In a study funded by the Michael J. Fox Foundation, researchers proposed a new disease designation: Neuronal alpha-synuclein disease (NSD) integrated staging system. It is characterized by these parameters:
- Synucleinopathy detected in CSF by SAA
- Dopaminergic dysfunction demonstrated by DaT-SPECT
- A fully penetrant SNCA gene variant
One primary goal is to define a homogeneous cohort for studies. However, only an estimated 10%-15% of patients likely have a monogenic background. Carriers of the pathogenic SNCA gene, in turn, make up only a fraction of these. The fully penetrant variants are even rarer.
- The second proposed classification, which takes biological markers into account, defines Parkinson’s disease according to the SynNeurGe criteria:
- S: Synucleinopathy
- N: Neurodegeneration
- G: GeneticsK: Clinic
- K: Clinic
Each patient is classified by combining these parameters. This system is intended to capture heterogeneity while making biological subtypes recognizable. According to this classification, the “classic” patient with sporadic Parkinson’s disease would be designated as S+/N+/G-.
Patients who meet the criteria for NSD represent a small subset of the patients who meet the SynNeurGe criteria.
“The biological definition opens, for the first time, the possibility of identifying patients before they develop symptoms and preventing disease progression or even averting the onset of the disease through prevention and early therapy,” Prasuhn summarized.
Berg revealed an insider detail at the end of the lecture: A framework concept developed by the DGN, not yet published, will integrate these two new disease concepts as well as clinical diagnoses.
This story was translated from Medscape’s German edition.
