WPC 2026 Update: The Current State of the Science - a New Way to Classify Parkinson’s Disease

Why researchers are moving beyond symptom-based diagnosis toward biological staging systems, disease subtypes, and precision medicine.

One of the most important themes I heard repeatedly at the World Parkinson Congress wasn't about a specific medication, gene, or scientific breakthrough.

It was about something much more fundamental:

How we classify Parkinson's disease.

For decades, Parkinson's disease has largely been diagnosed and staged based on what we can see.

How severe is the tremor?

How much has walking changed?

How much assistance does someone need?

How much disability is present?

Those questions remain incredibly important. But researchers are increasingly recognizing a major limitation:

Two people can look remarkably similar clinically while having very different disease biology.

And two people with very different symptoms may actually share many of the same underlying biological processes.

This realization is driving one of the biggest shifts currently occurring in Parkinson's research—the move from symptom-based classification toward biologic classification.

The Traditional Way We Stage Parkinson's Disease

Historically, clinicians have relied heavily on two major systems.

Hoehn & Yahr Staging

The Hoehn & Yahr scale was first developed in 1967 and remains one of the most widely recognized Parkinson's staging systems.

It focuses primarily on motor symptoms and overall disability.

The stages range from:

• Stage 1: Mild, unilateral symptoms

• Stage 2: Bilateral involvement

• Stage 3: Balance impairment develops

• Stage 4: Significant disability but able to walk independently

• Stage 5: Wheelchair dependence or need for substantial assistance

The system remains useful because it provides a simple snapshot of disease severity.

However, it has important limitations.

It tells us very little about cognition, sleep, autonomic dysfunction, mood, fatigue, pain, or many of the symptoms that often have the greatest impact on quality of life.

MDS-UPDRS

The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) provides a much more comprehensive assessment.

It evaluates:

• Motor symptoms

• Activities of daily living

• Non-motor symptoms

• Motor complications

The MDS-UPDRS remains the gold standard outcome measure used in both clinical practice and research.

But even this system measures what Parkinson's disease looks like—not necessarily what is happening biologically underneath.

The Problem With Symptom-Based Classification

One of the strongest messages throughout the conference was that symptoms often appear late in the disease process.

Researchers frequently referenced the idea that many people may lose 50% or more of their dopamine-producing neurons before developing recognizable motor symptoms.

If that is true, then traditional staging systems begin measuring disease only after substantial neurodegeneration has already occurred.

Imagine trying to stage heart disease only after someone develops heart failure.

Or trying to stage osteoporosis only after a hip fracture occurs.

That's essentially where Parkinson's disease has historically been.

Researchers are now trying to move the timeline much earlier.

Enter Biological Staging

The field is increasingly shifting toward biologic staging systems that focus on what is happening inside the body before symptoms become obvious.

Rather than asking:

"How severe are the symptoms?"

Researchers are beginning to ask:

"What biological processes are occurring right now?"

This is a fundamentally different way of thinking about Parkinson's disease.

The Alpha-Synuclein Revolution

Much of this shift has been driven by advances in biomarkers.

For the first time, researchers can identify evidence of abnormal alpha-synuclein accumulation in living people through:

• Cerebrospinal fluid testing

• Skin biopsies

• Seed amplification assays

These technologies allow researchers to identify biological evidence of Parkinson's-related pathology before traditional clinical diagnosis in some individuals.

This has created an entirely new framework for thinking about disease progression.

The NSD-ISS Framework

One of the most discussed systems at WPC was the Neuronal Synuclein Disease Integrated Staging System (NSD-ISS).

The goal of NSD-ISS is to create a biologically informed framework that captures disease progression before traditional symptoms appear.

Rather than focusing solely on visible symptoms, the system incorporates:

• Alpha-synuclein biomarkers

• Genetic risk factors

• Early clinical features

• Prodromal symptoms

• Motor symptoms

The hope is that this will allow researchers to identify individuals much earlier and intervene before significant neurodegeneration occurs.

While still primarily a research tool, many experts believe biologic staging systems will become increasingly important over the next decade.

Why Earlier Staging Matters

The importance of biologic staging becomes obvious when you consider disease-modifying therapies.

Most current experimental treatments are trying to:

• Reduce alpha-synuclein accumulation

• Improve lysosomal function

• Reduce inflammation

• Protect mitochondria

• Preserve neurons

But these therapies may work best before extensive neuronal loss has occurred.

If researchers can identify people earlier, future treatments may have a much greater chance of altering disease progression.

In other words:

Earlier diagnosis creates earlier opportunities for intervention.

Parkinson's Disease May Not Be One Disease

Perhaps the most fascinating concept discussed at the conference was that Parkinson's disease may actually represent multiple biologic diseases that produce similar symptoms.

This idea is beginning to reshape the field.

Historically, Parkinson's disease has been treated as a single disorder.

Researchers now increasingly suspect that what we call "Parkinson's disease" may actually represent several overlapping biological pathways leading to a similar clinical outcome.

This brings us to the concept of subtyping.

Brain-First vs Body-First Parkinson's Disease

One of the most exciting biologic subtype discussions involved the concept of Brain-First versus Body-First Parkinson's disease.

Brain-First Parkinson's Disease

In this model, pathology appears to begin within the central nervous system.

Alpha-synuclein accumulation may initially occur in structures such as:

• Amygdala

• Brainstem regions

• Central neural networks

Symptoms may emerge differently and biomarkers may follow a unique pattern.

Body-First Parkinson's Disease

In the body-first model, pathology may begin outside the brain.

Potential starting locations include:

• Gut nervous system

• Autonomic nervous system

• Peripheral nervous system

Researchers believe alpha-synuclein pathology may then gradually spread toward the brain.

This model may help explain why some individuals experience years of:

• Constipation

• REM Sleep Behavior Disorder

• Autonomic dysfunction

before motor symptoms appear.

Genetic Subtypes

Researchers are also increasingly identifying biologic subtypes based on genetics.

GBA1 Parkinson's Disease

GBA1-associated Parkinson's disease appears linked to lysosomal dysfunction and impaired protein clearance.

These patients may ultimately benefit from therapies specifically targeting GCase pathways.

LRRK2 Parkinson's Disease

LRRK2-associated Parkinson's disease involves abnormal protein activity that affects cellular maintenance and inflammatory pathways.

Multiple targeted therapies are currently being studied.

Mitochondrial Subtypes

Other forms of Parkinson's disease may involve stronger mitochondrial dysfunction and cellular energy failure.

Researchers continue exploring whether these individuals may respond differently to future therapies.

Clinical Subtypes Still Matter

While biologic subtyping is gaining momentum, clinical subtypes remain important.

Historically, clinicians have classified Parkinson's disease using motor patterns such as:

Tremor-Dominant

Symptoms are driven primarily by tremor.

PIGD-Dominant

Postural Instability and Gait Difficulty (PIGD) symptoms predominate.

However, researchers noted an important limitation.

Up to 50% of individuals may shift motor subtype classifications within only a few years.

These classifications also largely ignore non-motor symptoms.

The Rise of Non-Motor Subtyping

Many researchers now believe non-motor symptoms may provide important clues regarding disease biology.

Potential clinical subtypes include:

• Sleep-dominant

• Cognitive-dominant

• Pain and dystonia-dominant

• Autonomic-dominant

• Mood-dominant

These classifications better reflect the reality that Parkinson's disease affects far more than movement.

Multiple neurotransmitter systems become involved, including:

• Dopamine

• Norepinephrine

• Serotonin

• Cholinergic systems

• Autonomic pathways

• Sleep and circadian networks

This helps explain why no two people with Parkinson's disease look exactly alike.

The Future: Precision Medicine

All of these changes ultimately point toward one destination:

Precision medicine.

The goal is to move beyond the traditional model where every patient receives essentially the same treatment approach.

Instead, future care may involve identifying:

• Disease stage

• Biological subtype

• Genetic profile

• Biomarker status

• Dominant disease pathways

and then matching treatments accordingly.

The vision is similar to what has already occurred in cancer care, where biologic testing increasingly guides treatment decisions.

The Bigger Picture

One of the most important things I learned at the World Parkinson Congress is that researchers are no longer asking only:

"Does this person have Parkinson's disease?"

They are increasingly asking:

"What type of Parkinson's disease does this person have?"

That subtle shift may ultimately transform the future of diagnosis, research, and treatment.

For decades we have classified Parkinson's disease primarily by what we could observe.

Today, we are beginning to classify it by what is happening biologically beneath the surface.

And that shift may be one of the most important steps on the road toward earlier diagnosis, better clinical trials, more personalized therapies, and ultimately disease-modifying treatment.

Part 5: The Race Toward Disease-Modifying Therapies

An overview of the most promising approaches currently being tested, including alpha-synuclein therapies, LRRK2 inhibitors, anti-inflammatory treatments, mitochondrial therapies, and innovative platform trials.