ALS: What We Know Now About Its Early Stages and New Classification

If you or a loved one is affected by amyotrophic lateral sclerosis (ALS), you know how complex and challenging this disease can be. A recent review paper (published in Nature Reviews Neurology) offers new insights into how ALS develops—from its earliest, often unnoticeable stages to full-blown symptoms—and how doctors are rethinking its classification. This article breaks down the key findings in simple terms, focusing on what they mean for patients and families.

What You’ll Learn

This review summarizes a new framework for understanding ALS (called the Miami Framework) that:

• Explains how ALS overlaps with other brain disorders (like frontotemporal dementia, or FTD)
• Describes the prodromal (early) stages of ALS—signs that may appear before severe muscle weakness
• Highlights biomarkers (body signals) that could help predict disease progression
• Offers a roadmap for how doctors might diagnose and treat ALS earlier

A Quick Look at ALS

ALS is a neurodegenerative disease that damages motor neurons—the nerves that control muscles. As these neurons die, people with ALS experience progressive muscle weakness, difficulty speaking, swallowing, or breathing, and eventually loss of mobility. It’s often called “Lou Gehrig’s disease” after the famous baseball player who had it.

What makes ALS so complex? It doesn’t affect everyone the same way. Some people develop ALS alongside changes in behavior or thinking (a link to FTD), while others may have mild movement issues before muscle weakness starts. The new Miami Framework helps make sense of this variability.

Why Summarizing Research Like This Matters

ALS research is moving fast, but information can be scattered. This review brings together findings from hundreds of studies to create a unified view of ALS. For patients and families, this means:

• Clearer explanations of how ALS develops
• Hope for earlier diagnosis (before severe symptoms set in)
• Better conversations with doctors about care options

For researchers, it points to gaps in our knowledge and where to focus next.

What Does Current Research Say About ALS’s Early Stages and Classification?

The Miami Framework is the core of this review. It’s a new way to think about ALS that focuses on three “axes” of symptoms and the continuum of disease (from no symptoms to full ALS). Here’s what that means:

1. The Three “Axes” of ALS

ALS isn’t just a “muscle disease”—it can affect different parts of the brain and nervous system. The framework identifies three key areas (axes) where symptoms may appear:

• Motor Neuron Axis: The classic ALS symptoms—muscle weakness, twitching (fasciculations), or atrophy (muscle wasting).
• Frontotemporal Axis: Changes in behavior, personality, or thinking (e.g., apathy, trouble planning, or language problems). This is why some people with ALS develop FTD.
• Extrapyramidal Axis: Movement issues like tremors, stiffness, or difficulty with coordination (less common but important to recognize).

These axes can overlap—someone might have mild motor signs and early behavioral changes. The framework helps doctors track all three.

2. The ALS Continuum: From Pre-Symptomatic to Clinically Manifest

ALS doesn’t start suddenly. The review emphasizes a disease continuum with three stages:

• Clinically Silent: No noticeable symptoms, but biological changes (like nerve damage) may be happening.
• Prodromal: Early, mild signs that don’t yet meet ALS diagnostic criteria. Examples include:
  • Mild Motor Impairment (MMI): Subtle muscle twitching or weakness (detected by tests like EMG) without major disability.
  • Mild Cognitive Impairment (MCI): Trouble with memory or thinking that’s noticeable but not disabling.
  • Mild Behavioral Impairment (MBI): Small changes in behavior (e.g., losing interest in hobbies) that friends/family might notice.
• Clinically Manifest: Full-blown ALS symptoms (severe muscle weakness, difficulty breathing) that meet standard diagnostic criteria.

The key idea? Prodromal stages are real—and recognizing them could help start treatments earlier.

3. Biomarkers: What They Are and Why They Matter

Biomarkers are measurable signals in the body (like proteins in blood or cerebrospinal fluid, or brain scans) that indicate disease activity. The review highlights:

• Neurofilament Light Chain (NfL): A protein released when nerves are damaged. High levels in blood or CSF can predict faster disease progression.
• TDP-43 and Tau: Proteins linked to ALS and FTD. New tests are being developed to detect these in bodily fluids.

Biomarkers aren’t perfect yet—they can’t “diagnose” ALS on their own—but they’re a critical tool for tracking disease and testing new treatments.

What This Means for Patients and Families

The Miami Framework and new research on prodromal stages offer practical hope:

• Earlier Intervention: If prodromal signs are recognized, doctors might start treatments (like physical therapy or medications) sooner to slow progression.
• Better Care Planning: Understanding the three axes can help families prepare for changes in behavior, movement, or cognition.
• Personalized Care: The framework acknowledges that ALS is different for everyone—treatment can be tailored to an individual’s symptoms.

It also means asking better questions of your doctor:

• “Could my mild muscle twitching be a prodromal sign?”
• “Should I get tested for biomarkers like NfL?”
• “How can we monitor changes in my thinking or behavior?”

Gaps in Our Knowledge & Future Directions

The review is clear: we still have a lot to learn. Key gaps include:

• Prodromal Criteria: There’s no universal definition for MMI, MCI, or MBI in ALS. Researchers need more data to create standardized tests.
• Biomarker Trajectories: We don’t yet know exactly when biomarkers (like NfL) rise in the prodromal stage—or how they correlate with symptoms.
• Generalizability: Most research focuses on genetic forms of ALS. We need to learn more about non-genetic (sporadic) ALS.

Future research will focus on filling these gaps—with the goal of making prodromal diagnosis and early treatment a reality for all people with ALS.

Key Points to Remember

1. ALS is a spectrum: It can affect motor neurons, behavior/cognition, and movement—often at the same time.
2. Prodromal stages exist: Mild signs (like muscle twitching or subtle behavior changes) may appear before severe symptoms.
3. Biomarkers are promising: Tests for proteins like NfL could help predict progression and guide treatment.
4. The Miami Framework helps: It’s a new way for doctors to track ALS and tailor care to each patient.

Talk to Your Doctor

This review is a tool—not a replacement for medical advice. If you’re concerned about ALS (or prodromal signs), talk to your neurologist. They can:

• Perform tests (like EMG or blood work) to check for signs of nerve damage
• Discuss whether biomarker testing is right for you
• Help you create a care plan that addresses all aspects of your health

Remember: You’re not alone. ALS research is advancing, and the more we understand about its early stages, the better we can fight it.

Stay informed, ask questions, and keep hope alive.