The Braak staging system is a neuropathological grading method developed by German anatomist Heiko Braak to describe the progression of major neurodegenerative diseases. This system classifies the degree of pathology by mapping the predictable, anatomical spread of misfolded proteins within the brain and nervous system. By analyzing post-mortem brain tissue, researchers can assign a stage to an individual, offering a framework for understanding the pathology and progression of conditions like Alzheimer’s and Parkinson’s disease.
The Proteins That Define Disease Spread
The Braak staging system relies on the observation that specific proteins misfold and accumulate in a sequential pattern unique to each disease. In Alzheimer’s disease, the central protein is Tau, which aggregates into neurofibrillary tangles (NFTs) inside neurons. For Parkinson’s disease, the pathology involves Alpha-synuclein, which misfolds to form Lewy bodies and Lewy neurites.
The systematic spread is often described as “prion-like propagation.” This concept suggests that misfolded protein aggregates move from one nerve cell to a neighboring, healthy cell, templating the misfolding of the native protein. This cell-to-cell transfer through synaptically connected regions creates the observed, stereotypical pattern of anatomical progression. The staging systems track this orderly propagation, providing a biological basis for the progression of symptoms over time.
Mapping Alzheimer’s Progression
The Braak stages for Alzheimer’s disease (AD) track the spread of Tau-based neurofibrillary tangles (NFTs) through six distinct stages, moving from memory centers outward.
Stages I and II
These stages mark the earliest pathology, with NFTs primarily confined to the transentorhinal and entorhinal regions. These regions are deeply involved in memory and are often affected before cognitive symptoms become apparent.
Stages III and IV
The pathology progresses to the limbic system, characterized by the involvement of the hippocampus and other limbic structures. The hippocampus is crucial for forming new memories, and its involvement often corresponds with the initial signs of mild cognitive impairment.
Stages V and VI
The disease reaches its most advanced form, where neurofibrillary tangles have spread extensively into the neocortical regions. This widespread cortical involvement reflects the severe cognitive decline and clinical dementia that define late-stage Alzheimer’s disease.
Mapping Parkinson’s Progression
The Braak staging system for Parkinson’s disease (PD) tracks the spread of Alpha-synuclein pathology (Lewy bodies) through six stages, starting from the lower brainstem and ascending toward the cortex.
Stages 1 and 2
These stages represent the earliest pathological changes, with Lewy bodies first appearing in the dorsal motor nucleus of the vagus nerve and the anterior olfactory nucleus. This initial involvement correlates with early, non-motor symptoms such as constipation and a reduced sense of smell, which can precede motor symptoms by many years.
Stage 3
The pathology ascends into the midbrain, affecting the substantia nigra and the amygdala. The substantia nigra produces dopamine, and its degeneration causes the motor symptoms—tremor, rigidity, and slowness—associated with a clinical PD diagnosis.
Stages 4, 5, and 6
These stages mark the disease’s continued spread into higher brain regions. Pathology starts with the mesocortex and thalamus in Stage 4, culminating in the diffuse involvement of the neocortex in Stages 5 and 6. This extensive cortical spread correlates with the onset of severe physical disability and Parkinson’s disease dementia.
Why Braak Stages Matter to Researchers
The Braak stages are a foundational tool for researchers, providing a standardized, post-mortem method for assessing disease severity and confirming a neuropathological diagnosis. This systematic staging allows for consistent comparison of brain tissue across different studies globally. The system is valuable for understanding the temporal sequence of disease development, suggesting the pathological process begins years, or even decades, before the onset of motor or cognitive symptoms.
The staging framework is now being adapted for use in living patients through advanced imaging techniques like tau-Positron Emission Tomography (PET). This helps researchers track the spread of pathology in real-time. The ability to stage the disease in a preclinical phase guides the design of clinical trials aimed at early intervention to halt the pathological spread. However, researchers acknowledge that the pathological stage does not always perfectly align with a patient’s clinical symptoms or cognitive decline, indicating that other factors influence the manifestation of the disease.