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重新定义帕金森病的生物学分类与治疗的未来

医药生物 2025-07-29 Atuka 坚守此念

Parkinson’s disease (PD) research is shifting from clinical definitions to a biologically based classification system, driven by novel biomarkers and a deeper understanding of the disease's complex pathology, particularly in the prodromal (pre-symptomatic) phase. This shift is crucial for developing disease modifying therapies (DMTs) and improving disease modelling.

The need for a biological classification of PD

Historically, PD and related Lewy body disorders have been defined primarily by clinical features, leading to challenges such as slow diagnosis, heterogeneity, and lack of objectivity. This reliance on clinical symptoms often means that DMT trials are conducted when significant neurodegeneration has already occurred, hindering efforts to develop effective treatments.

Proposed biological classification systems for PD

Two prominent biology-based criteria for PD have recently been proposed:

SynNeurGe framework: This system uses a three-component biological system linked to a clinical component to classify PD and related Lewy body disorders. The components are:
- S (Synucleinopathy status): Indicates the presence or absence of pathological α-synuclein using methods like Seed Amplification Assays (SAA) and skin biopsies.
- N (Neurodegeneration status): Provides evidence of underlying neurodegeneration through neuroimaging procedures such as DAT imaging, metabolic FDG-PET, and cardiac MIBG SPECT.
- G (Genetic status): Documents the presence or absence of pathogenic gene variants using methods like genetic testing.
- C (Clinical status): Defined by either a single high-specificity clinical feature or multiple lower-specificity clinical features, determining if they are attributable to the underlying biological process of PD.
Neuronal α-Synuclein Disease (NSD) concept, including the Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS): This concept defines neuronal α-synuclein disease as the presence of pathological α-synuclein and stage-dependent evidence of dopaminergic neuronal dysfunction. It uses S and D as primary biological anchors, with genetic status (G) playing a supporting role, and functional impairment defining later stages.

Similarities and differences between SynNeurGe and NSD-ISS

Both systems aim to improve early diagnosis and facilitate the development of DMTs. However, they differ in terminology, aims, methodology, and the scope of PD they encompass. SynNeurGe is broader and more flexible, while NSD-ISS is more restricted and focused on early sporadic PD.

Continued development of biological classifications of PD

Both frameworks are expected to evolve over time, incorporating advancements in biomarkers, non-invasive testing, new biological anchors, and more longitudinal data. Understanding the prodromal features, the progression of pathology, and the intersectionality of different biological factors will be crucial for refining these classifications.

Use of biological classifications in research

Both SynNeurGe and NSD-ISS can be used to produce more homogeneous clinical trial populations by removing individuals who are unlikely to have early-stage PD. This can improve the power of clinical trials and accelerate the development of DMTs. The choice of classification will depend on the specific research question being addressed.

Ethical implications of biological classification for PD

The transition to biological diagnosis, especially in asymptomatic individuals, raises ethical concerns such as limited understanding of natural history, lack of approved DMTs, diagnostic inaccuracy, commercialization, and technological demands. Addressing these concerns requires careful consideration and the involvement of key stakeholders.

Impact of biological classifications on preclinical research

The shift towards a biological classification of PD will drive a deeper understanding of the different types of disease processes underlying the disease. This will allow for the development of more accurate animal models and the identification of new therapeutic targets. Understanding the initial cell loss and the specific biological processes affected at different stages of the disease will be crucial for developing effective DMTs.

Impact on developing symptomatic therapies

While animal models have been successful in developing symptomatic therapies for motor symptoms, the development of therapies for non-motor symptoms may require a greater incorporation of the emerging biology of the disease. The heterogeneity of non-motor symptoms and the limited understanding of their underlying pathology present challenges that need to be addressed.

RedefiningParkinson’sDisease Biological Classification and theFuture of Therapeutics A primer on the emerging biological understanding of Parkinson’sand its possible impact on the development of novel therapeuticsand disease modelling. ByPatrick A. Howson, PhDChief Innovation Officer How Biological Classification is Redefining Parkinson’s DiseaseHow Biological Classification is Redefining Parkinson’s Disease Contents The need for a biological classification of Parkinson’s Disease3Proposed biological classification systems for Parkinson’s Disease5The SynNeurGe research diagnostic criteria5The Neuronalα-Synuclein Disease Integrated Staging System (NSD-ISS)10Similarities and differences between SynNeurGe and NSD-ISS14Continued development of biological classifications of Parkinson’sdisease17Use of biological classifications in research20Ethical implications of biological classification for PD21Impact of biological classifications on preclinical research22Impact on developing disease modifying therapies22Impact on developing symptomatic therapies25Summary28References29 How B iological Classification is Redefining Parkinson’s Disease Parkinson’s disease (PD) research is undergoinga significant shift from traditional clinicaldefinitions to a biologically based classificationsystem. This change is driven by novelbiomarkers developed around a deeperunderstanding of the disease’s complexpathology, particularly in the prodromal (pre-symptomatic) phase. This phase begins decades before clinical symptoms appear and thedisease is diagnosed. Ultimately, this shift is allowing researchersto create a PD framework that will facilitate more comprehensivedisease modelling, drive biomarker development, encourage morefocused therapeutic targeting, optimize clinical trial design, betteralign preclinical and clinical research and, ultimately, enableprecision medicine—as in medical care designed to optimizetherapeutic benefits for an individual. In this first Atuka white paper on the subject, we will be providingan overview of the current state of biological classificationsin PD. We will also consider potential future areas of researchthat will be used to elaborate, refine, and augment the currentbiological classifications. We will also briefly discuss the impactthat a biological classification of PD may have on preclinical drugdevelopment. In future white papers we will explore these topics inmore depth. The need for a biological classification ofParkinson’s Disease Historically, PD and related Lewy body disorders, such asdementia with Lewy bodies (DLB), have been defined primarilyby their clinical features. Diagnostic criteria for PD have relied onobservable motor symptoms, such as bradykinesia, rigidity, andresting tremor, which typically manifest only after a substantialloss (60–80%) of nigral dopaminergic neurons has alreadyoccurred. This reliance on clinical symptoms presents severalchallenges: How B iological Classification is Redefining Parkinson’s Disease >Slow diagnosis:Thedisease pathology (e.g.,α-synuclein aggregation andneurodegeneration) often beginslong before symptoms appear,meaning clinical criteria cannotcapture these pre-symptomaticor prodromal stages. Thus,performing disease modifyingtrials in people most likely tobenefit, such as those in theearliest stages of the disease isdifficult. >Heterogeneity:Clinicalsyndromes and theirprogression are highlyheterogeneous, leading tooverlap among differentneurodegenerative disorders.This can lead to the inclusion ofpeople in clinical trials withoutPD, which increases noisewithin the data and reduces thepower of the trial. >Lack of objectivity:Clinicaldiagnoses can be subjective andprone to misclassification, as clinical phenotypes may resultfrom different underlying pathologies. As above, this canlead to the inclusion of people in clinical trials without PD,increasing noise and reducing the power of clinical trials. The exclusive reliance on clinical diagnosis, without adequatebiological stratification, is probably a contributing factor to why adisease modifying therapy (DMT) has not been developed for PD. AsDMTs aim to interfere with the molecular and cellular mechanismsthat lead to neuronal dysfunction and degeneration, a biologicalunderstanding of PD is necessary for their development, along witha better understanding of the heterogeneity of biology across peoplewith PD, and how the biology changes as the disease progresses. A biological classification of PD offers several advantages,including objectivity, homogeneity of patient populations forresearch, earlier diagnosis (potentially before symptom onset),and patient stratification based on biology, which is essential for How B iological Classification is Redefining Parkinson’s Disease developing targeted precision therapies. Such a system can servemultiple clinical purposes: defining the disease entity, providingdiagnosis, stratifying patients into subgroups, and potentiallyclassifying patients ac

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